Azabicyclic-substituted-heteroaryl compounds for the treatment of disease

ABSTRACT

The invention provides compounds of Formula I: 
     Azabicyclo-N(R 1 )—C(═X)—W  Formula I 
     These compounds may be in the form of pharmaceutical salts or compositions, racemic mixtures, or pure enantiomers thereof. The compounds of Formula I are useful in pharmaceuticals in which α7 is known to be involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisionalapplication Serial No. 60/336,977, filed on Nov. 8, 2001, under 35 USC119(e)(i), U.S. provisional application Serial No. 60/350,108 filed onNov.13, 2001, under 35 USC 119(e)(i), U.S. provisional applicationSerial No. 60/357,906, filed on Feb. 19 , 2002, under 35 USC 119(e)(i),U.S. provisional application Serial No. 60/358,142 filed on Feb.19,2002, under 35 USC 119(e)(i), and U.S. provisional application SerialNo. 60/358,159 filed on Feb. 19, 2002, under 35 USC 119(e)(i), which areincorporated herein by reference in their entirety.

FIELD OF INVENTION

[0002] Nicotinic acetylcholine receptors (nAChRs) play a large role incentral nervous system (CNS) activity. Particularly, they are known tobe involved in cognition, learning, mood, emotion, and neuroprotection.There are several types of nicotinic acetylcholine receptors, and eachone appears to have a different role in regulating CNS function.Nicotine affects all such receptors, and has a variety of activities.Unfortunately, not all of the activities are desirable. In fact, one ofthe least desirable properties of nicotine is its addictive nature andthe low ratio between efficacy and safety. The present invention relatesto molecules that have a greater effect upon the α7 nAChRs as comparedto other closely related members of this large ligand-gated receptorfamily. Thus, the invention provides compounds that are active drugmolecules with fewer side effects.

BACKGROUND OF THE INVENTION

[0003] U.S. Pat. No. 6,441,049 B2 disclsoes a method of treatingnerodegenerative disorders via inhibition of amyloid beta peptidebinding.

[0004] U.S. Pat. No. 6,255,490 B 1 discloses 7-azabicyclo[2.2.1]-heptaneand—heptene derivatives as cholinergic receptor ligands.

[0005] U.S. Pat. No. 6,060,473 discloses7-azabicyclo[2.2.1]-heptaneand—heptene derivatives as cholinergic receptor ligands.

[0006] U.S. Pat. No. 6,054,464 discloses azabicyclic esters of carbamicacids useful in therapy, especially in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, as well asintermediates and use of intermediates in synthesis.

[0007] U.S. Pat. No. 5,977,144 discloses compositions for benzylidene-and cinnamylidene-anabaseines and methods for using these compositionsfor treating conditions associated with defects or malfunctioning ofnicotinic subtypes brain receptors. These compositions target the α7receptor subtype with little or no activation of the α4β2 or otherreceptor subtypes.

[0008] U.S. Pat. No. 5,712,270 discloses a group of 2-aroylaminothiazolederivatives which bind to and stimulate central muscarinic acetylcholinereceptors and are useful agents for treating symptoms of cognitivedisorders, specifically the impaired memory associated with a decreasein the neurotransmitter, acetylcholine. Some of the compounds of thisinvention also bind to 5HT_(1A) receptors and dopamine D₂ receptors,making them useful as antipsychotic agents.

[0009] U.S. Pat. No. 5,624,941 discloses pyrazole derivatives useful inpharmaceuticals in which cannabis is known to be involved.

[0010] U.S. Pat. No. 5,561,149 discloses the use of a mono or bicycliccarbocyclic, or heterocyclic carboxylic, acid ester or amide or animidazolyl carbazol in the manufacture of a medicament suitable for thetreatment of stress-related psychiatric disorders, for increasingvigilance, for the treatment of rhinitis or serotonin-induced disordersand/or coadministration with another active agent to increase thebioavailability thereof, or for nasal administration.

[0011] U.S. Pat. No. 5,510,478 discloses a group of 2-aroylaminothiazolederivatives which bind to and stimulate central muscarinic acetylcholinereceptors and are useful agents for treating symptoms of cognitivedisorders, specifically the impaired memory associated with a decreasein the neurotransmitter, acetylcholine. Some of the compounds of thisinvention also bind to 5HT_(1A) receptors and dopamine D₂ receptors,making them useful as antipsychotic agents.

[0012] U.S. Pat. No. 5,364,863 discloses bicyclic carboxylic esters andamides, their pharmaceutical formulations, and a method for their use intreating migraine, emesis, gastrointestinal-disorders, schizophrenia, oranxiety in mammals.

[0013] U.S. Pat. No. 5,217,975 discloses azabicyclic compounds fortreating dementia.

[0014] U.S. Pat. No. 5,106,843 discloses heterocyclic compounds usefulas 5-HT₃ antagonists.

[0015] U.S. Pat. No. 5,057,519 discloses 5-HT₃ antagonists as beinguseful in reducing opiate tolerance.

[0016] U.S. Pat. No. 5,039,680 discloses 5-HT₃ antagonists in preventingor reducing dependency on dependency-inducing agents.

[0017] U.S. Pat. No. 4,988,691 discloses isoxazole-containing compoundsexhibiting anti-serotonin activity.

[0018] U.S. Pat. No. 4,921,982 discloses5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which areuseful as intermediates for 5-HT₃ antagonists.

[0019] U.S. Pat. No. 4,863,919 discloses a method of enhancing memory orcorrecting memory deficiency with arylamido- (andarylthioamido-)azabicyclalkanes.

[0020] U.S. Pat. No. 4,835,162 discloses agonists and antagonists tonicotine as smoking deterrents.

[0021] U.S. Pat. No. 4,605,652 discloses a method of enhancing memory orcorrecting memory deficiency with arylamido (andarylthioamido)-azabicycloalkanes, and the pharmaceutically acceptableacid addition salts, hydrates and alcoholates thereof.

[0022] U.S. patent No. application 2002/0016334 discloses apharmaceutical composition for the treatment of attention deficithyperactivity disorder.

[0023] WO 01/60821 discloses novel biarylcarboxamides.

[0024] WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives anduse in therapy, especially in the treatment of prophylaxis of psychoticdisorders and intellectual impairment disorders.

[0025] WO 01/29304 discloses quinuclidine acrylamides.

[0026] WO 00/73431 A2 discloses two binding assays to directly measurethe affinity and selectivity of compounds at the α7 nAChR and the5-HT₃R. The combined use of these functional and binding assays may beused to identify compounds that are selective agonists of the α7 nAChR.

[0027] WO 98/54189 discloses spiro-quinuclidine derivatives, theirpreparation and use.

[0028] WO 97/30998 discloses azabicyclic esters of carbamic acids usefulin therapy.

[0029] WO 95/01793 discloses 5-HT₃ antagonists as topical medicamentsfor treatment of peripheral disorders associated with pain.

[0030] WO 92/15579 discloses multicyclic tertiary amine polyaromaticsqualene synthase inhibitors and method of treatment for lowering serumcholesterol levels using the compounds.

[0031] WO 92/21339 discloses isoxazole and isothiazole compounds thatenhance cognitive function.

[0032] JP 04-247081 discloses 5-membered heterocyclic acid amides.

[0033] In Bioorg. & Med. Chem. Lett. 11 (2001) 319-321, the 5-HT₃antagonist tropisetron (ICS 205-930) is discussed as a potent andselective α7 Nicotinic receptor partial agonist.

[0034] In Behavioral Brain Res., 113 (2000) 169-181, it is discussedthat the brain α7 nicotinic receptor may be an important therapeutictarget for the treatment of Alzheimer's disease using DMXBA which isknown as GTS-21.

[0035] In J Med. Chem., 40 (1997), 4169-4194, neuronal nicotinicacetylcholine receptors are discussed as targets for drug discovery.

[0036] In Science, 279 (1998), 77-81, the broad-spectrum, non-opioidanalgesic activity is discussed by selective modulation of neuronalnicotinic acetylcholine receptors.

[0037] Cell surface receptors are, in general, excellent and validateddrug targets. nAChRs comprise a large family of ligand-gated ionchannels that control neuronal activity and brain function. Thesereceptors have a pentameric structure. In mammals, this gene family iscomposed of nine alpha and four beta subunits that co-assemble to formmultiple subtypes of receptors that have a distinctive pharmacology.Acetylcholine is the endogenous regulator of all of the subtypes, whilenicotine non-selectively activates all nAChRs.

[0038] The α7 nAChR is one receptor system that has proved to be adifficult target for testing. Native α7 nAChR is not routinely able tobe stably expressed in most mammalian cell lines (Cooper and Millar, JNeurochem., 1997, 68(5):2140-51). Another feature that makes functionalassays of α7 nAChR challenging is that the receptor is rapidly (100milliseconds) inactivated. This rapid inactivation greatly limits thefunctional assays that can be used to measure channel activity.

[0039] Recently, Eisele et al. has indicated that a chimeric receptorformed between the N-terminal ligand binding domain of the α7 nAChR(Eisele et al., Nature, 366(6454), p 479-83, 1993), and the pore formingC-terminal domain of the 5-HT₃ receptor expressed well in Xenopusoocytes while retaining nicotinic agonist sensitivity. Eisele et al.used the N-terminus of the avian (chick) form of the α7 nAChR receptorand the C-terminus of the mouse form of the 5-HT₃ gene. However, underphysiological conditions the α7 nAChR is a calcium channel while the5-HT₃R is a sodium and potassium channel. Indeed, Eisele et al. teachesthat the chicken α7 nAChR/mouse 5-HT₃R behaves quite differently thanthe native α7 nAChR with the pore element not conducting calcium butactually being blocked by calcium ions. WO 00/73431 A2 reports on assayconditions under which the 5-HT₃R can be made to conduct calcium. Thisassay may be used to screen for agonist activity at this receptor.

SUMMARY OF THE INVENTION

[0040] The present invention discloses compounds of the Formula I:

Azabicyclo-N(R₁)—C(═X)—W Formula I

[0041] wherein, X is O or S;

[0042] R₁ is H, alkyl, cycloalkyl, halogenated alkyl, or aryl;

[0043] W is a cyclic heteroaromatic moiety where the heteroatoms can befrom 1-2 atoms selected from oxygen, sulfur, or nitrogen of thefollowing structures:

[0044] wherein U is —O—, —S—, or —N(Ru)—;

[0045] V and Y are independently ═N—, or ═C(Rvy)—;

[0046] Z is ═N—, or ═CH—, provided that when both V and Y are═C(R_(vy))—and Z is ═CH—, only one ═C(R_(vy))— can be ═CH—, furtherprovided that when U is —O—, Y is ═C(R_(vy))— and Z is ═C(H)—, V cannotbe ═N—, and further provided that no more than one of V, Y, or Z is aheteroatom;

[0047] R_(u) is H, alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substitutedalkyl, limited substituted alkyl, substituted cycloalkyl, substitutedheterocycloalkyl, aryl, or —SO₂R₈, and provided that when W is (b) and Zis ═N— and U is N(R_(u)), R_(u) cannot be phenyl or substituted phenyl;

[0048] Each R_(vy) is independently H, alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkenyl,halogenated alkynyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, substituted alkenyl, substitutedalkynyl, substituted cycloalkyl, substituted heterocycloalkyl, limitedsubstituted alkyl, limited substituted alkenyl, limited substitutedalkynyl, aryl, —OR₈, —OR₁₄, —SR₈, —SR₁₄, F, Cl, Br, I, —NR₈R₈, —NR₁₄R₁₄,—C(O)R₈, —C(O)R₁₄, —C(O)NR₈R₈, —C(O)NR₁₄R₁₄, —C(R₆)═N(R₁₆), —CN,—NR₈C(O)R₁₁, —S(O)₂NR₈R₈, —OS(O)₂R₁₁, —S(O)₂R₈, —S(O)₂R₁₄,—NR₈S(O)₂R₈,—N(H)C(O)N(H)R₈, —NO₂,R₇,R₉, and 0-3 substituentsindependently selected from F, Cl, Br, I, or R₁₅, and 0-3 substituentsindependently selected from F, Cl, Br, I, or R₁₅;

[0049] Azabicyclo is

[0050] R₀ is H, lower alkyl, substituted lower alkyl, or halogenatedlower alkyl;

[0051] R₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,aryl or R₂ is absent provided that k₂, k₅, or k₆ is 0;

[0052] k₂ is 0 or 1;

[0053] k₅ and k₆ are independently 0, 1, or 2;

[0054] R₂₋₃ is H, alkyl, halogenated alkyl, substituted alkyl, F, Cl,Br, or I;

[0055] R₆ is H, F, Cl, CN, alkyl, substituted alkyl, cycloalkyl,halogenated alkyl, and aryl;

[0056] R₇ is 5-membered heteroaromatic mono-cyclic moieties containingwithin the ring 1-3 heteroatoms independently selected from the groupconsisting of —O—, ═N—, —N(R₁₉)—, and —S—, and having 0-1 substituentselected from R₂₀ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I, or R₇ is a 9-membered fused-ring moietyhaving a 6-membered ring fused to a 5-membered ring and having theformula

[0057] wherein A₁ is O, S, or NR_(19,)

[0058] wherein A is CR₁₈ or N, A₂ and A₃ are independently selected fromCR₁₈, C(R₁₈)₂, O, S, N, or NR₁₉, provided that both A₂ and A₃ are notsimultaneously O, simultaneously S, or simultaneously O and S, or

[0059] wherein A is CR₁₈ or N, A₂ and A₃ are independently selected fromCR₁₈, C(R₁₈)₂, O, S, N, or NR₁₉, each 9-membered fused-ring moietyhaving 0-1 substituent selected from R₂₀ and further having 0-3substituent(s) independently selected from F, Cl, Br, or I, and having abond directly or indirectly attached to the core molecule where valencyallows in either the 6-membered or the 5-membered ring of the fused-ringmoiety;

[0060] Each R₈ is independently H, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl;

[0061] R₉ is 6-membered heteroaromatic mono-cyclic moieties containingwithin the ring 1-3 heteroatoms selected from ═N— and having 0-1substituent selected from R₂₀ and 0-3 substituent(s) independentlyselected from F, Cl, Br, or I, or R₉ is 10-membered heteroaromaticbi-cyclic moieties containing within one or both rings 1-3 heteroatomsselected from ═N—, including, but not limited to, quinolinyl orisoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituentselected from R₂₀ and 0-3 substituent(s) independently selected from F,Cl, Br, or I, and having a bond directly or indirectly attached to thecore molecule where valency allows;

[0062] Each R₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl,alkyl substituted with 1 substituent selected from R₁₃, cycloalkylsubstituted with 1 substituent selected from R₁₃, heterocycloalkylsubstituted with 1 substituent selected from R₁₃, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, R₇, R₉, orphenyl having 1 substituent selected from R₂₀ and further having 0-3substituents independently selected from F, Cl, Br, or I;

[0063] Each R₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, or halogenatedheterocycloalkyl;

[0064] R₁₃ is —OR₁₁, —SR₁₁, —NR₁₁ R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁,—CN,—NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, —CF₃, or —NO_(2;)

[0065] Each R₁₄ is independently H, alkyl, halogenated alkyl, limitedsubstituted alkyl, cycloalkyl, halogenated cycloalkyl, substitutedcycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, orsubstituted heterocycloalkyl;

[0066] R₁₅ is alkyl, substituted alkyl, halogenated alkyl, —OR₁₁, —CN,—NO₂, —NR₁₀R₁₀;

[0067] R₁₆ is —OR₁₇, —NR₁₇R₁₇, —NR₁₇C(O)R₁₇, —NR₁₇S(O)₂R₁₇, —N(R₁₇)C(O)NR₁₇R₁₇, —NR₁₇C(O)OR_(17;)

[0068] R₁₇ is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedheterocycloalkyl, phenyl, phenyl having 1-4 substituents independentlyselected from F, Cl, Br, I and R₁₅, naphthyl, or naphthyl having 1-4substituents independently selected from F, Cl, Br, I and R_(15;)

[0069] Each R₁₈ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl,—OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,—S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, F, Cl, Br, or I, or a bond directly orindirectly attached to the core molecule, provided that there is onlyone said bond to the core molecule within the 9-membered fused-ringmoiety, further provided that the fused-ring moiety has 0-1 substituentselected from alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁,—NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁,C(O)R₁₁,—S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁, and further provided that thefused-ring moiety has 0-3 substituent(s) selected from F, Cl, Br, or I;

[0070] R₁₉ is H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl,—SO₂R₈, or phenyl having 1 substituent selected from R₂₀ and furtherhaving 0-3 substituents independently selected from F, Cl, Br, or I;

[0071] R₂₀ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, —OR₁, —SR₁₁,—NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁,—NR₁₁S(O)₂R₁₁, —NO₂, alkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R₁₃, cycloalkyl substitutedwith 1-4 substituent(s) independently selected from F, Cl, Br, I, orR₁₃, or heterocycloalkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R_(13;)

[0072] or pharmaceutical composition, pharmaceutically acceptable salt,racemic mixture, or pure enantiomer thereof.

[0073] Embodiments of the invention may include one or more orcombination of the following.

[0074] An embodiment of the present invention provides a use of acompound of Formula I for treating a disease or condition, wherein thediseases, disorders, and/or condition is any one or more or combinationof the following: cognitive and attention deficit symptoms ofAlzheimer's Disease, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problems ingeneral and associated with brain tumors, AIDS dementia complex,dementia associated with Down's syndrome, dementia associated with LewyBodies, Huntington's disease, Parkinson's disease, tardive dyskinesia,Pick's disease, dysregulation of food intake including bulemia andanorexia nervosa, withdrawal symptoms associated with smoking cessationand dependant drug cessation, Gilles de la Tourette's Syndrome,age-related macular degeneration, glaucoma, neurodegeneration associatedwith glaucoma, or symptoms associated with pain.

[0075] In another aspect, the invention includes treating a mammalsuffering from schizophrenia or psychosis by administering compounds ofFormula I in conjunction with antipsychotic drugs (also calledanti-psychotic agents). The compounds of the present invention and theantipsychotic drugs can be administered simultaneously or at separateintervals. When administered simultaneously the compounds of the presentinvention and the antipsychotic drugs can be incorporated into a singlepharmaceutical composition. Alternatively, two separate compositions,i.e., one containing compounds of the present invention and the othercontaining antipsychotic drugs, can be administered simultaneously.

[0076] The present invention also includes the compounds of the presentinvention, pharmaceutical compositions containing the active compoundsas the free base or as a pharmaceutically acceptable salt and apharmaceutically acceptable carrier, and methods to treat the identifieddiseases.

[0077] A further embodiment of the present invention provides a methodcomprising administering a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositioncontains said compound to the mammal.

[0078] The present invention also includes a pharmaceutical compositioncomprising a compound of Formula I or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable excipient. The pharmaceuticalcomposition is administered rectally, topically, orally, sublingually,or parenterally for a therapeutically effective interval. Thepharmaceutical composition is administered to deliver a compound of thepresent invention in an amount of from about 0.001 to about 100 mg/kg ofbody weight of said mammal per day. The pharmaceutical composition isalso administered to deliver a compound of the present invention in anamount of from about 0.1 to about 50 mg/kg of body weight of said mammalper day.

[0079] A pharmaceutical composition comprising a compound of Formula Ior a pharmaceutically acceptable salt thereof, an anti-psychotic agent,and a pharmaceutically acceptable excipient. The pharmaceuticalcomposition is administered to independently administer said compoundand said agent rectally, topically, orally, sublingually, orparenterally for a therapeutically effective interval. Thepharmaceutical composition is administered to deliver a compound of thepresent invention in an amount of from about 0.001 to about 100 mg/kg ofbody weight of said mammal per day. The pharmaceutical composition isalso administered to deliver a compound of the present invention in anamount of from about 0.1 to about 50 mg/kg of body weight of said mammalper day.

[0080] The present invention also includes a use of a compound accordingto Formula I or pharmaceutically acceptable salt thereof for thepreparation of a medicament for treating a disease or condition, whereinthe mammal would receive symptomatic relief from the administration of atherapeutically effective amount of α7 nicotinic acetylcholine receptoragonist.

[0081] The present invention also includes a use of a compound accordingto Formula I or pharmaceutically acceptable salt thereof for thepreparation of a medicament for treating a disease or condition, whereinthe mammal would receive symptomatic relief from the administration of atherapeutically effective amount of α7 nicotinic acetylcholine receptoragonist, wherein the disease, or condition is any one or more orcombination of the following: cognitive and attention deficit symptomsof Alzheimer's Disease, neurodegeneration associated with diseases suchas Alzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problems ingeneral and associated with brain tumors, AIDS dementia complex,dementia associated with Down's syndrome, dementia associated with LewyBodies, Huntington's disease, Parkinson's disease, tardive dyskinesia,Pick's disease, dysregulation of food intake including bulemia andanorexia nervosa, withdrawal symptoms associated with smoking cessationand dependant drug cessation, Gilles de la Tourette's Syndrome,age-related macular degeneration, glaucoma, neurodegeneration associatedwith glaucoma, or symptoms associated with pain.

[0082] The present invention also includes a method for treating adisease or condition in a mammal in need thereof, wherein the mammalwould receive symptomatic relief from the administration of an α7nicotinic acetylcholine receptor agonist comprising administering to themammal a therapeutically effective amount of a compound according toFormula I or pharmaceutically acceptable salt thereof.

[0083] The present invention also includes a method for treating adisease or condition in a mammal in need thereof comprisingadministering to the mammal a therapeutically effective amount of acompound according to Formula I or pharmacecutically acceptable saltthereof, wherein the disease or condition is any one or more orcombination of the following: cognitive and attention deficit symptomsof Alzheimer's Disease, neurodegeneration associated with diseases suchas Alzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problems ingeneral and associated with brain tumors, AIDS dementia complex,dementia associated with Down's syndrome, dementia associated with LewyBodies, Huntington's disease, Parkinson's disease, tardive dyskinesia,Pick's disease, dysregulation of food intake including bulemia andanorexia nervosa, withdrawal symptoms associated with smoking cessationand dependant drug cessation, Gilles de la Tourette's Syndrome,age-related macular degeneration, glaucoma, neurodegeneration associatedwith glaucoma, or symptoms associated with pain.

[0084] Another embodiment of the present invention includes compoundswhere X is O or S.

[0085] Another embodiment of the present invention includes compoundswhere R₁₁ is H, alkyl, or cycloalkyl.

[0086] Another embodiment of the present invention includes compoundswhere Azabicyclo is any one or more of I, II, III, IV, V, or VI.

[0087] Another embodiment of the present invention includes compoundswhere R₂ is lower alkyl or is absent provided that k₂, k₅ or k₆ is 0;and where R₂₋₃ is H or lower alkyl.

[0088] Another embodiment of the present invention includes compoundswhere W is (a) or (b).

[0089] Another embodiment of the present invention includes compoundswhere (a) is thiophen-2-yl, furan-2-yl, 1,3-thiazol-5-yl, or1,3-oxazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-oxadiazol-2-yl,1,3-oxazol-5-yl, 1H-pyrrol-2-yl, or 1,2,4-oxadiazol-5-yl,

[0090] any of which is optionally substituted on carbon independentlywith alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl,halogenated heterocycloalkyl, substituted alkyl, substituted alkenyl,substituted alkynyl, substituted cycloalkyl, substitutedheterocycloalkyl, limited substituted alkyl, limited substitutedalkenyl, limited substituted alkynyl, aryl, —OR₈, —OR₁₄, —SR₈, —SR₁₄, F,Cl, Br, I, —NR₈R₈, —NR₁₄R₁₄, —C(O)R₈, —C(O)R₁₄, —C(O)NR₈R₈,—C(O)NR₁₄R₁₄, —C(R₆)═N(R₁₆), —CN, —NR₈C(O)R₁₁, —S(O)₂NR₈R₈, —OS(O)₂R₁₁,—S(O)₂R₈, —S(O)₂R₁₄, —NR₈S(O)₂R₈, —N(H)C(O)N(H)R₈, —NO₂, R₇, R₉, and 0-3substituents independently selected from F, Cl, Br, I, or R₁₅, and 0-3substituents independently selected from F, Cl, Br, I, or R₁₅; andfurther optionally substituted on nitrogen with alkyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, limited substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, aryl, or —SO₂R₈.One of ordinary skill in the art can identify where substituents areallowed according to Formula I.

[0091] Another embodiment of the present invention includes compoundswhere (b) is 1,3-thiazol-4-yl, 1,3-oxazol-4-yl, 1H-1,2,4-triazol-3-yl,or isoxazol-3-yl,

[0092] any of which is optionally substituted on carbon independentlywith alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl,halogenated heterocycloalkyl, substituted alkyl, substituted alkenyl,substituted alkynyl, substituted cycloalkyl, substitutedheterocycloalkyl, limited substituted alkyl, limited substitutedalkenyl, limited substituted alkynyl, aryl, —OR₈, —OR₁₄, —SR₈, —SR₁₄, F,Cl, Br, I, —NR₈R₈, —NR₁₄R₁₄, —C(O)R₈, —C(O)R₁₄, —C(O)NR₈R₈,—C(O)NR₁₄R₁₄, —C(R₆)═N(R₁₆), —CN, —NR₈C(O)R₁₁, —S(O)₂NR₈R₈, —OS(O)₂R₁₁,—S(O)₂R₈, —S(O)₂R₁₄, —NR₈S(O)₂R₈, —N(H)C(O)N(H)R₈, —NO₂, R₇, R₉, and 0-3substituents independently selected from F, Cl, Br, I, or R₁₅, and 0-3substituents independently selected from F, Cl, Br, I, or R₁₅; andfurther optionally substituted on nitrogen with alkyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, limited substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, aryl, or —SO₂R₈.One of ordinary skill in the art can identify where substituents areallowed according to Formula I.

[0093] Another embodiment of the present invention includes compoundswhere R_(u) is any one or more of the following: H, alkyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, limited substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, aryl, or —SO₂R₈,and provided that when W is (b) and Z is ═N— and U is N(R_(u)), R_(u)cannot be phenyl or substituted phenyl.

[0094] Another embodiment of the present invention includes compoundswhere each R_(vy) is independently any one or more of the following: H,alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl,halogenated heterocycloalkyl, substituted alkyl, substituted alkenyl,substituted alkynyl, substituted cycloalkyl, substitutedheterocycloalkyl, limited substituted alkyl, limited substitutedalkenyl, limited substituted alkynyl, aryl, —OR₈, —OR₁₄, —SR₈, —SR₁₄, F,Cl, Br, I, —NR₈R₈, —NR₁₄R₁₄, —C(O)R₈, —C(O)R₁₄, —C(O)NR₈R₈,—C(O)NR₁₄R₁₄, —C(R₆)═N(R₁₆), —CN, —NR₈C(O)R₁₁, —S(O)₂NR₈R₈, —OS(O)₂R₁₁,—S(O)₂R₈, —S(O)₂R₁₄, —NR₈S(O)₂R₈, —N(H)C(O)N(H)R₈, —NO₂, R₇, R₉, and 0-3substituents independently selected from F, Cl, Br, I, or R₁₅, and 0-3substituents independently selected from F, Cl, Br, I, or R_(15.)

[0095] Another embodiment of the present invention includes thecompounds where R₆ is any one or more of the following: H, F, Cl, CN,alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, and aryl.

[0096] Another embodiment of the present invention includes thecompounds where each R₈ is independently any one or more of thefollowing: H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,halogenated heterocycloalkyl, substituted heterocycloalkyl, R₇, R₉,phenyl, or substituted phenyl.

[0097] Another embodiment of the present invention includes thecompounds where each R₁₁ is independently any one or more of thefollowing: H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, or halogenated heterocycloalkyl.

[0098] Another embodiment of the present invention includes thecompounds where each R₁₄ is independently any one or more of thefollowing: H, alkyl, halogenated alkyl, limited substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, or substitutedheterocycloalkyl.

[0099] Another embodiment of the present invention includes thecompounds where (a) is any one or more of the following: thiophen-2-yl,furan-2-yl, 1,3-thiazol-2-yl, 1,3-oxazol-2-yl, or 1H-pyrrol-2-yl, any ofwhich is optionally substituted with up to 2 substituents wherein thesubstituents are bromo, chloro, methyl, phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-aminophenyl, 3-aminophenyl,4-aminophenyl, 2-acetylaminophenyl, 3-acetylaminophenyl,4-acetylaminophenyl, 2-trifluoroacetamidophenyl,3-trifluoroacetamidophenyl, 4-trifluoroacetamidophenyl, or pyridinyl.One of ordinary skill in the art can identify where substituents areallowed according to Formula I.

[0100] Another embodiment of the present invention includes any one ormore of the following compounds as the free base or a pharmaceuticallyacceptable salt there of and as the pure enantiomer or as a racemicmixture thereof:

[0101]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromothiophene-2-carboxamide;

[0102]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-bromothiophene-2-carboxamide;

[0103]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(pyridin-2-yl)-thiophene-2-carboxamide;

[0104]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenylthiophene-2-carboxamide;

[0105] N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-2-furamide;

[0106]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)-2-furamide;

[0107] N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-2-furamide;

[0108]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)-2-furamide;

[0109]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)-2-furamide;

[0110]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)-2-furamide;

[0111]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)-2-furamide;

[0112]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide;

[0113]5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0114]5-(4-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;or

[0115]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide.

[0116] Another embodiment of the present invention includes any one ormore of the following compounds as the free base or a pharmaceuticallyacceptable salt there of and as the pure enantiomer or as a racemicmixture thereof:

[0117]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-chlorothiophene-2-carboxamide;

[0118]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-methylthiophene-2-carboxamide;

[0119]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenylthiophene-2-carboxamide;

[0120]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;

[0121]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;

[0122]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;

[0123]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;

[0124]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;

[0125]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;

[0126]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;

[0127]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;

[0128]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;

[0129]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;

[0130]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;

[0131]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;

[0132]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;

[0133]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;

[0134]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;

[0135]5-(2-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;

[0136]5-(3-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;

[0137]5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;

[0138]5-(2-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;

[0139]5-(3-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;

[0140]5-(4-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;

[0141]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0142]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0143]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0144] N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromo-2-furamide;

[0145] N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-chloro-2-furamide;

[0146] N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-methyl-2-furamide;

[0147]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-fluorophenyl)-2-furamide;

[0148]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-fluorophenyl)-2-furamide;

[0149]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-chlorophenyl)-2-furamide;

[0150]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-chlorophenyl)-2-furamide;

[0151]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-chlorophenyl)-2-furamide;

[0152]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methoxyphenyl)-2-furamide;

[0153]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methoxyphenyl)-2-furamide;

[0154]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methoxyphenyl)-2-furamide;

[0155]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methylphenyl)-2-furamide;

[0156]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methylphenyl)-2-furamide;

[0157]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methylphenyl)-2-furamide;

[0158]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-hydroxyphenyl)-2-furamide;

[0159]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-hydroxyphenyl)-2-furamide;

[0160]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-hydroxyphenyl)-2-furamide;

[0161]5-(2-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;

[0162]5-(3-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;

[0163]5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;

[0164]5-(2-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;

[0165]5-(3-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;

[0166]5-(4-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;

[0167]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;

[0168]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;

[0169]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;

[0170]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromo-1,3-thiazole-2-carboxamide;

[0171]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-chloro-1,3-thiazole-2-carboxamide;

[0172]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-methyl-1,3-thiazole-2-carboxamide;

[0173]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1,3-thiazole-2-carboxamide;

[0174]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0175]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0176]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0177]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0178]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0179]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0180]N-[(3R,5R)-1-azabicycio[3.2.1]oct-3-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0181]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0182]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0183]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;

[0184]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;

[0185]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;

[0186]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0187]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0188]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0189]5-(2-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0190]5-(3-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0191]5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0192]5-(2-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0193]5-(3-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0194]5-(4-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0195]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0196]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0197]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0198]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromo-1,3-oxazole-2-carboxamide;

[0199]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-chloro-1,3-oxazole-2-carboxamide;

[0200]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-methyl-1,3-oxazole-2-carboxamide;

[0201]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0202]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0203]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0204]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0205]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0206]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0207]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0208]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0209]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0210]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;

[0211]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;

[0212]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;

[0213]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0214]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0215]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0216]5-(2-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0217]5-(3-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0218]5-(2-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0219]5-(3-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0220]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0221]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0222]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0223]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1H-pyrrole-2-carboxamide;or

[0224]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1-methyl-1H-pyrrole-2-carboxamide.

[0225] Another embodiment of the present invention includes any one ormore of the following compounds as the free base or a pharmaceuticallyacceptable salt there of and as the pure enantiomer or as a racemicmixture thereof:

[0226]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-chlorothiophene-2-carboxamide;

[0227]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-methylthiophene-2-carboxamide;

[0228]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;

[0229]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;

[0230]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;

[0231]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;

[0232]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;

[0233]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;

[0234]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;

[0235]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;

[0236]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;

[0237]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;

[0238]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;

[0239]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;

[0240]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;

[0241]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;

[0242]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;

[0243]5-(2-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;

[0244]5-(3-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;

[0245]5-(4-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;

[0246]5-(2-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;

[0247]5-(3-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;

[0248]5-(4-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;

[0249]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0250]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0251]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0252] N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-2-furamide;

[0253] N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-chloro-2-furamide;

[0254] N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-methyl-2-furamide;

[0255]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-chlorophenyl)-2-furamide;

[0256]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)-2-furamide;

[0257]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-chlorophenyl)-2-furamide;

[0258]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methoxyphenyl)-2-furamide;

[0259]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methoxyphenyl)-2-furamide;

[0260]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methoxyphenyl)-2-furamide;

[0261]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylphenyl)-2-furamide;

[0262]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methylphenyl)-2-furamide;

[0263]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)-2-furamide;

[0264]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)-2-furamide;

[0265]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-hydroxyphenyl)-2-furamide;

[0266]5-(2-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;

[0267]5-(3-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;

[0268]5-(4-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;

[0269]5-(2-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;

[0270]5-(3-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;

[0271]5-(4-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;

[0272]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;

[0273]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;

[0274]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;

[0275]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-1,3-thiazole-2-carboxamide;

[0276]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-chloro-1,3-thiazole-2-carboxamide;

[0277]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-methyl-1,3-thiazole-2-carboxamide;

[0278]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1,3-thiazole-2-carboxamide;

[0279]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0280]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0281]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0282]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0283]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0284]N-[(exo-4(S))-1-azabicyclo[2.2.1]bept-3-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0285]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0286]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0287]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0288]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;

[0289]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;

[0290]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;

[0291]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0292]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0293]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0294]5-(2-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;

[0295]5-(3-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;

[0296]5-(4-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;

[0297]5-(2-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;

[0298]5-(3-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;

[0299]5-(4-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;

[0300]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0301]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0302]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0303]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-1,3-oxazole-2-carboxamide;

[0304]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-chloro-1,3-oxazole-2-carboxamide;

[0305]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-methyl-1,3-oxazole-2-carboxamide;

[0306]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0307]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0308]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0309]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0310]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0311]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0312]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0313]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0314]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0315]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;

[0316]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;

[0317]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;

[0318]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0319]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0320]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0321]5-(2-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;

[0322]5-(3-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;

[0323]5-(4-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;

[0324]5-(2-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;

[0325]5-(3-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;

[0326]5-(4-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;

[0327]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0328]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0329]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0330]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1H-pyrrole-2-carboxamide;or

[0331]N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1-methyl-1H-pyrrole-2-carboxamide.

[0332] Another embodiment of the present invention includes any one ormore of the following compounds as the free base or a pharmaceuticallyacceptable salt there of and as the pure enantiomer or as a racemicmixture thereof:

[0333]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-bromothiophene-2-carboxamide;

[0334]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-chlorothiophene-2-carboxamide;

[0335]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-methylthiophene-2-carboxamide;

[0336]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenylthiophene-2-carboxamide;

[0337]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;

[0338]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;

[0339]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyI)thiophene-2-carboxamide;

[0340]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)thlophene-2-carboxamide;

[0341]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;

[0342]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;

[0343]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;

[0344]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)tbiophene-2-carboxamide;

[0345]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;

[0346]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;

[0347]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;

[0348]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;

[0349]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;

[0350]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-hydroxyphenyl)tbiophene-2-carboxamide;

[0351]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;

[0352]5-(2-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;

[0353]5-(3-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;

[0354]5-(4-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;

[0355]5-(2-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;

[0356]5-(3-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;

[0357]5-(4-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;

[0358]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0359]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0360]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0361] N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-2-furamide;

[0362]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-2-furamide;

[0363]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-methyl-2-fuiramide;

[0364]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-2-furamide;

[0365]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)-2-furamide;

[0366]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)-2-furamide;

[0367]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-2-furamide;

[0368]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-2-furamide;

[0369]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-2-furamide;

[0370]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-2-furamide;

[0371]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)-2-furamide;

[0372]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-2-furamide;

[0373]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)-2-furamide;

[0374]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)-2-furamide;

[0375]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)-2-furamide;

[0376]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)-2-furamide;

[0377]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)-2-furamide;

[0378]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-hydroxyphenyl)-2-furamide;

[0379]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-hydroxyphenyl)-2-furamide;

[0380]5-(2-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;

[0381]5-(3-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;

[0382]5-(4-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;

[0383]5-(2-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;

[0384]5-(3-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;

[0385]5-(4-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-fuiramide;

[0386]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;

[0387]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;

[0388]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;

[0389]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,3-thiazole-2-carboxamide;

[0390]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1,3-thiazole-2-carboxamide;

[0391]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-methyl-1,3-thiazole-2-carboxamide;

[0392]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1,3-thiazole-2-carboxamide;

[0393]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0394]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0395]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0396]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0397]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0398]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0399]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0400]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0401]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0402]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;

[0403]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;

[0404] N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)-,3-thiazole-2carboxamide;

[0405]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0406]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0407]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0408]5-(2-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0409]5-(3-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0410]5-(4-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0411]5-(2-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0412]5-(3-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0413]5-(4-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;

[0414]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0415]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0416]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0417]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,3-oxazole-2-carboxamide;

[0418]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1,3-oxazole-2-carboxamide;

[0419]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-methyl-1,3-oxazole-2-carboxamide;

[0420]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide;

[0421]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0422]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0423]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0424]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0425]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0426]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0427]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0428]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0429]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0430]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;

[0431]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;

[0432]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;

[0433]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0434]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0435]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0436]5-(2-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0437]5-(3-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0438]5-(4-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0439]5-(2-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0440]5-(3-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0441]5-(4-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;

[0442]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0443]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0444]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0445]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1H-pyrrole-2-carboxamide;

[0446]N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1-methyl-1H-pyrrole-2-carboxamide;or

[0447]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide.

[0448] Another embodiment of the present invention includes any one ormore of the following compounds as the free base or a pharmaceuticallyacceptable salt there of and as the pure enantiomer or as a racemicmixture thereof:

[0449] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-bromothiophene-2-carboxamide;

[0450] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-chlorothiophene-2-carboxamide;

[0451] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-methylthiophene-2-carboxamide;

[0452] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenylthiophene-2-carboxamide;

[0453]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;

[0454]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;

[0455]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;

[0456]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;

[0457]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;

[0458]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;

[0459]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;

[0460]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;

[0461]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;

[0462]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;

[0463]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;

[0464]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;

[0465]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;

[0466]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;

[0467]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;

[0468]5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;

[0469]5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;

[0470]5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;

[0471]5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;

[0472]5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;

[0473]5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;

[0474]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0475]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0476]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0477] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-bromo-2-furamide;

[0478] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-chloro-2-furamide;

[0479] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-methyl-2-furamide;

[0480] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-2-furamide;

[0481] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-fluorophenyl)-2-furamide;

[0482] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-fluorophenyl)-2-furamide;

[0483] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-fluorophenyl)-2-furamide;

[0484] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-chlorophenyl)-2-furamide;

[0485] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-chlorophenyl)-2-furamide;

[0486] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-chlorophenyl)-2-furamide;

[0487] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methoxyphenyl)-2-furamide;

[0488] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methoxyphenyl)-2-furamide;

[0489] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methoxyphenyl)-2-furamide;

[0490] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methylphenyl)-2-furamide;

[0491] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methylphenyl)-2-furamide;

[0492] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methylphenyl)-2-furamide;

[0493] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-hydroxyphenyl)-2-furamide;

[0494] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-hydroxyphenyl)-2-furamide;

[0495] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-hydroxyphenyl)-2-furamide;

[0496] 5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;

[0497] 5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;

[0498] 5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;

[0499]5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;

[0500]5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;

[0501]5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;

[0502]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;

[0503]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;

[0504]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;

[0505]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-bromo-1,3-thiazole-2-carboxamide;

[0506]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-chloro-1,3-thiazole-2-carboxamide;

[0507]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-methyl-1,3-thiazole-2-carboxamide;

[0508]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-1,3-thiazole-2-carboxamide;

[0509]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0510]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0511]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0512]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0513]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0514]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0515]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0516]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0517]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0518]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;

[0519]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;

[0520]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;

[0521]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0522]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0523]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0524]5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;

[0525]5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;

[0526]5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;

[0527]5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;

[0528]5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;

[0529]5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;

[0530]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0531]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0532]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0533]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-bromo-1,3-oxazole-2-carboxamide;

[0534]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-chloro-1,3-oxazole-2-carboxamide;

[0535]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-methyl-1,3-oxazole-2-carboxamide;

[0536]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-1,3-oxazole-2-carboxamide;

[0537] N-[2-azabicyclo[2.21]hept-5-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0538]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0539]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0540]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0541]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0542]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0543]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0544]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0545]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0546]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;

[0547]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;

[0548]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;

[0549] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0550] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0551] N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0552]5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;

[0553]5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;

[0554]5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;

[0555]5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;

[0556]5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;

[0557]5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;

[0558]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0559]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0560]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0561]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-1H-pyrrole-2-carboxamide; or

[0562]N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-1-methyl-1H-pyrrole-2-carboxamide.

[0563] Another embodiment of the present invention includes any one ormore of the following compounds as the free base or a pharmaceuticallyacceptable salt there of and as the pure enantiomer or as a racemicmixture thereof:

[0564] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-bromothiophene-2-carboxamide;

[0565] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-chlorothiophene-2-carboxamide;

[0566] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-methylthiophene-2-carboxamide;

[0567] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenylthiophene-2-carboxamide;

[0568]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;

[0569]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;

[0570]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;

[0571]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;

[0572]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;

[0573]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;

[0574]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;

[0575]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;

[0576]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;

[0577]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;

[0578]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;

[0579]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;

[0580]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;

[0581]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;

[0582]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;

[0583]5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;

[0584]5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;

[0585]5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;

[0586]5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;

[0587]5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;

[0588]5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;

[0589]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0590]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0591]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;

[0592] N-[2-azabicyclo[2.2.1]hept-6-yll-5-bromo-2-furamide;

[0593] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-chloro-2-furamide;

[0594] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-methyl-2-furamide;

[0595] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-2-furamide;

[0596] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-fluorophenyl)-2-furamide;

[0597] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-fluorophenyl)-2-furamide;

[0598] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-fluorophenyl)-2-furamide;

[0599] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-chlorophenyl)-2-furamide;

[0600] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-chlorophenyl)-2-furamide;

[0601] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-chlorophenyl)-2-furamide;

[0602] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methoxyphenyl)-2-furamide;

[0603] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methoxyphenyl)-2-furamide;

[0604] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methoxyphenyl)-2-furamide;

[0605] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methylphenyl)-2-furamide;

[0606] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methylphenyl)-2-furamide;

[0607] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methylphenyl)-2-furamide;

[0608] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-hydroxyphenyl)-2-fuiramide;

[0609] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-hydroxyphenyl)-2-furamide;

[0610] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-hydroxyphenyl)-2-furamide;

[0611] 5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;

[0612] 5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;

[0613] 5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;

[0614]5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;

[0615]5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;

[0616]5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;

[0617]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;

[0618]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;

[0619]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;

[0620]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-bromo-1,3-thiazole-2-carboxamide;

[0621]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-chloro-1,3-thiazole-2-carboxamide;

[0622]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-methyl-1,3-thiazole-2-carboxamide;

[0623]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-1,3-thiazole-2-carboxamide;

[0624]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0625]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0626]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;

[0627]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0628]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0629]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;

[0630]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0631]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0632]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;

[0633]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;

[0634]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;

[0635]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;

[0636]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0637]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide

[0638]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;

[0639]5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;

[0640]5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;

[0641]5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;

[0642]5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;

[0643]5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;

[0644]5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;

[0645]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0646]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0647]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;

[0648]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-bromo-1,3-oxazole-2-carboxamide;

[0649]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-chloro-1,3-oxazole-2-carboxamide;

[0650]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-methyl-1,3-oxazole-2-carboxamide;

[0651]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-1,3-oxazole-2-carboxamide;

[0652]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0653]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0654]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;

[0655]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0656]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0657]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;

[0658]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0659]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0660]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;

[0661]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;

[0662]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;

[0663]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;

[0664] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0665] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0666] N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;

[0667]5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;

[0668]5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;

[0669]5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;

[0670]5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;

[0671]5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;

[0672]5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;

[0673]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0674]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0675]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;

[0676]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-1H-pyrrole-2-carboxamide; or

[0677]N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-1-methyl-1H-pyrrole-2-carboxamide.

[0678] The compounds of Formula I (Azabicyclo is I) have asymmetriccenters on the quinuclidine ring. The compounds of the present inventioninclude quinuclidines with the 3R configuration and also includesracemic mixtures and compositions of varying degrees of streochemicalpurities. For example, and not by limitation, compounds of Formula Iinclude compounds with stereospecificity including:

[0679] The compounds of Formula I (Azabicyclo is II) have asymmetriccenters on the [2.2.1]azabicyclic ring at C3 and C4. The scope of thisinvention includes racemic mixtures and the separate stereoisomers ofFormula I being endo-4S, endo-4R, exo-4S, exo-4R:

[0680] The endo isomer is the isomer where the non-hydrogen substituentat C3 of the [2.2.1]azabicyclic compound is projected toward the largerof the two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C3 of the [2.2.1]azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-4(R), exo-4(S), endo-4(R), andendo-4(S).

[0681] The compounds of Formula I (Azabicyclo III) have asymmetriccenters on the [2.2.1]azabicyclic ring at C1, C4 and C5. The scope ofthis invention includes racemic mixtures and the separate stereoisomersof Formula I being (1R,4R,5S), (1R,4R,5R), (1S,4S,5R), (1S,4S,5S):

[0682] The endo isomer is the isomer where the non-hydrogen substituentat C5 of the [2.2.1]azabicyclic compound is projected toward the largerof the two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C5 of the [2.2.1]azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-(1R,4R,5S), exo-(1S,4S,5R),endo-(1S,4S,5S), endo-(1R,4R,5R).

[0683] The compounds of Formula I (Azabicyclo IV) have asymmetriccenter(s) on the [2.2.1]azabicyclic ring at C1, C4 and C6. The scope ofthis invention includes racemic mixtures and the separate stereoisomersof Formula I being exo-(1S,4R,6S), exo-(1R,4S,6R), endo-(1S,4R,6R), andendo-(1R,4S,6S):

[0684] The endo isomer is the isomer where the non-hydrogen substituentat C6 of the [2.2.1]azabicyclic compound is projected toward the largerof the two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C6 of the [2.2.1]azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-(1S,4R,6S), exo-(1R,4S,6R),endo-(1S,4R,6R), and endo-(1R,4S,6S).

[0685] The compounds of Formula I (Azabicyclo is V) have asymmetriccenter(s) on the [3.2.1]azabicyclic ring at C3 and C5. The scope of thisinvention includes racemic mixtures and the separate stereoisomers ofFormula I being endo-3S, 5R, endo-3R, 5S, exo-3R, 5R, exo-3S, 5S:

[0686] The compounds of Formula I (Azabicyclo is VI) have asymmetriccenters on the [3.2.2]azabicyclic ring with one center being at C3 whenR₂ is absent. The scope of this invention includes racemic mixtures andthe separate stereoisomers of Formula I being 3(S) and 3(R):

[0687] The compounds of the present invention having the specifiedstereochemistry have different levels of activity and that for a givenset of values for the variable substitutuents one isomer may bepreferred over the other isomers. Although it is desirable that thestereochemical purity be as high as possible, absolute purity is notrequired. This invention involves racemic mixtures and compositions ofvarying degrees of streochemical purities when the Azabicyclo issubstituted with only the amide/thioamide or is substituted withsubstituents in addition to the amide/thioamide, e.g., k is 1 or 2. Thisinvention involves racemic mixtures and compositions of varying degreesof stereochemical purities. When racemic mixtures and compositions arereferenced, it means racemic mixtures and compositions of varying degreeof stereochemical purities. It is preferred to carry out stereoselectivesyntheses and/or to subject the reaction product to appropriatepurification steps so as to produce substantially enantiomerically purematerials. Suitable stereoselective synthetic procedures for producingenantiomerically pure materials are well known in the art, as areprocedures for purifying racemic mixtures into enantiomerically purefractions. Naming a specific isomer includes racemic mixtures thereofwithin the scope of this invention. Therefore, namingN-(exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl)-5-bromo-thiophene-2-carboxamideincludesN-(exo-4(rac)-1-azabicyclo[2.2.1]hept-3-yl)-5-bromo-thiophene-2-carboxamide,N-((3-rac)-4(S)-1-azabicyclo[2.2.1]hept-3-yl)-5-bromo-thiophene-2-carboxamideand N-((rac)1-azabicyclo[2.2.1]hept-3-yl)-5-bromo-thiophene-2-carboxamide.

[0688] Stereoselective syntheses and/or subjecting the reaction productto appropriate purification steps produces substantiallyenantiomerically pure materials. Suitable stereoselective syntheticprocedures for producing enantiomerically pure materials are well knownin the art, as are procedures for purifying racemic mixtures intoenantiomerically pure fractions.

[0689] Another embodiment of the compounds of Formula I includes any oneor more or combination of the following configurations for compounds:

[0690] where (i) the compound is a racemic mixture, or

[0691] (ii) the compound has the R stereochemistry at C-3 as discussedherein and stereochemistry is unspecified at C-6.

[0692] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for compounds:

[0693] where (i) k₂ is 0 (R₂ is absent);

[0694] (ii) R₂ has any definition discussed herein;

[0695] (iii) R₂ has any definition discussed herein; or

[0696] (iv) the 2.2.1 moiety has the exo-4(S) stereochemistry asdiscussed herein.

[0697] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for compounds:

[0698] where (i) R₂₋₃ is H;

[0699] (ii) R₂₋₃ is F, Cl, Br, I, alkyl, halogenated alkyl, substitutedalkyl, or substituted phenyl or substituted naphthyl; or

[0700] (iii) R₂₋₃ is alkyl, halogenated alkyl, substituted alkyl, orsubstituted phenyl or substituted naphthyl.

[0701] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for compounds:

[0702] where (i) R₂₋₃ is H;

[0703] (ii) R₂₋₃ is F, Cl, Br, I, alkyl, halogenated alkyl, substitutedalkyl, or substituted phenyl or substituted naphthyl; or

[0704] (iii) R₂₋₃ is alkyl, halogenated alkyl, substituted alkyl, orsubstituted phenyl or substituted naphthyl.

[0705] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for compounds:

[0706] where (i) k₅ is 0 (R₂ is absent);

[0707] (ii) R₂ is absent and where the Azabicyclo has thestereochemistry of 3R, 5R;

[0708] (iii) k₅ is 2, where R₂ is R_(2-a) and R_(2-b), both of whichhave any definition discussed herein for R₂;

[0709] (iv) k₅ is 1, where R₂ has any definition discussed herein; or

[0710] (v) k₅ is 1, where R₂ has any definition discussed herein.

[0711] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for compounds:

[0712] where (i) k₆ is 0 (R₂ is absent);

[0713] (ii) k₆ is 2, where R₂ is R_(2-a) and R_(2-b), both of which haveany definition discussed herein for R₂;

[0714] (iii) k₆ is 1, where R₂ has any definition discussed herein; or

[0715] (iv) k₆ is 1, where R₂ has any definition discussed herein.

[0716] It has further surprisingly been found that the compounds of thepresent invention having the N-[1-azabicyclo[2.2.1]heptyl moietygenerally have better metabolic stability than the correspondingcompound with quinuclidinyl as the azabicyclic moiety.

[0717] Further aspects and embodiments of the invention may becomeapparent to those skilled in the art from a review of the followingdetailed description, taken in conjunction with the examples and theappended claims. While the invention is susceptible of embodiments invarious forms, described hereafter are specific embodiments of theinvention with the understanding that the present disclosure is intendedas illustrative, and is not intended to limit the invention to thespecific embodiments described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0718] Surprisingly, we have found that compounds of Formula I:

Azabicyclo-N(R₁)-C(═X)-W  Formula I

[0719] wherein, X is O or S;

[0720] R₁ is H, alkyl, cycloalkyl, halogenated alkyl, or aryl;

[0721] W is a cyclic heteroaromatic moiety where the heteroatoms can befrom 1-2 atoms selected from oxygen, sulfur, or nitrogen of thefollowing structures:

[0722] wherein U is —O—, —S—, or —N(R_(U))—;

[0723] V and Y are independently ═N—, or ═C(R_(VY))—;

[0724] Z is ═N—, or ═CH—, provided that when both V and Y are═C(R_(VY))— and Z is ═CH—, only one ═C(R_(VY))— can be ═CH—, furtherprovided that when U is —O—, Y is ═C(R_(VY))— and Z is ═C(H)—, V cannotbe ═N—, and further provided that no more than one of V, Y, or Z is aheteroatom;

[0725] R_(U) is H, alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substitutedalkyl, limited substituted alkyl, substituted cycloalkyl, substitutedheterocycloalkyl, aryl, or —SO₂R₈, and provided that when W is (b) and Zis ═N— and U is N(R_(U)), R_(U) cannot be phenyl or substituted phenyl;

[0726] Each R_(VY) is independently H, alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkenyl,halogenated alkynyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, substituted alkenyl, substitutedalkynyl, substituted cycloalkyl, substituted heterocycloalkyl, limitedsubstituted alkyl, limited substituted alkenyl, limited substitutedalkynyl, aryl, —OR₈, —OR₁₄, —SR₈, —SR₁₄, F, Cl, Br, I, —NR₈R₈, —NR₁₄R₁₄,—C(O)R₈, —C(O)R₁₄, —C(O)NR₈R₈, —C(O)NR₁₄R₁₄, —C(R₆)═N(R₁₆), —CN,—NR₈C(O)R₁₁, —S(O)₂NR₈R₈, —OS(O)₂R₁₁, —S(O)₂R₈, —S(O)₂R₁₄, —NR₈S(O)₂R₈,—N(H)C(O)N(H)R₈, —NO₂, R₇, R₉, and 0-3 substituents independentlyselected from F, Cl, Br, I, or R₁₅, and 0-3 substituents independentlyselected from F, Cl, Br, I, or R₁₅;

[0727] Azabicyclo is

[0728] R₀ is H, lower alkyl, substituted lower alkyl, or halogenatedlower alkyl;

[0729] R₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,aryl or R₂ is absent provided that k₂, k₅, or k₆ is 0;

[0730] k₂is0or 1;

[0731] k₅ and k₆ are independently 0, 1, or 2;

[0732] R₂₋₃ is H, alkyl, halogenated alkyl, substituted alkyl, F, Cl,Br, or I;

[0733] Alkyl is both straight and branched-chain moieties having from1-6 carbon atoms;

[0734] Halogenated alkyl is an alkyl moiety having from 1-6 carbon atomsand having 1 to (2n+1) substituent(s) independently selected from F, Cl,Br, or I, where n is the maximum number of carbon atoms in the moiety;

[0735] Substituted alkyl is an alkyl moiety having from 1-6 carbon atomsand having 0-3 substituents independently selected from F, Cl, Br, or I,and further having 1 substituent selected from R₇, R₉, —OR₁₀, —SR₁₀,—NR₁₀R₁₀, —C(O)R₁₀, —NO₂, —C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀,—S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituentselected from R₂₀ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I;

[0736] Limited substituted alkyl is a substituted alkyl having from 1-6carbon atoms and having 0-3 substituents independently selected from F,Cl, Br, or I, and further having 1 substituent on either only the et)carbon and selected from —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —NO₂,—C(O)NR₁₁R₁₁, —CN, —NR₁₀C(O)R₁₁, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, or on anycarbon with sufficient valency but not on the ω carbon and selected fromR₇, R₉, —OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —NO₂, —C(O)NR₁₀R₁₀, —CN,—NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I;

[0737] Alkenyl is straight and branched-chain moieties having from 2-6carbon atoms and having at least one carbon-carbon double bond;

[0738] Halogenated alkenyl is an unsaturated alkenyl moiety having from2-6 carbon atoms and having 1 to (2n−1) substituent(s) independentlyselected from F, Cl, Br, or I, where n is the maximum number of carbonatoms in the moiety;

[0739] Substituted alkenyl is an unsaturated alkenyl moiety having from2-6 carbon atoms and having 0-3 substituents independently selected fromF, or Cl, and further having 1 substituent selected from R₇, R₉, —OR₁₀,—SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀,—S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituentselected from R₂₀ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I;

[0740] Limited substituted alkenyl is a substituted alkenyl having from1-6 carbon atoms and having 0-3 substituents independently selected fromF, Cl, Br, or I, and further having 1 substituent on either only the ωcarbon and selected from —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —NO₂,—C(O)NR₁₁R₁₁, —CN, —NR₁₀C(O)R₁₁, —S(O)₂NR₁₀R₁₀, or —NR₁₀S(O)₂R₁₀, or onany carbon with sufficient valency but not on the ω carbon and selectedfrom R₇, R₉, —OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —NO₂, —C(O)NR₁₀R₁₀, —CN,—NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I;

[0741] Alkynyl is straight and branched-chain moieties having from 2-6carbon atoms and having at least one carbon-carbon triple bond;

[0742] Halogenated alkynyl is an unsaturated alkynyl moiety having from3-6 carbon atoms and having 1 to (2n−3) substituent(s) independentlyselected from F, Cl, Br, or I, where n is the maximum number of carbonatoms in the moiety;

[0743] Substituted alkynyl is an unsaturated alkynyl moiety having from3-6 carbon atoms and having 0-3 substituents independently selected fromF, or Cl, and further having 1 substituent selected from R₇, R₉, —OR₁₀,—SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —CN, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀,—S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituentselected from R₂₀ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I;

[0744] Limited substituted alkynyl is a substituted alkynyl having from1-6 carbon atoms and having 0-3 substituents independently selected fromF, Cl, Br, or I, and further having 1 substituent on either only the ωcarbon and selected from —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —NO₂,—C(O)NR₁₁R₁₁, —CN, —NR₁₀C(O)R₁₁, —S(O)₂NR₁₀R₁₀, or —NR₁₀S(O)₂R₁₀, or onany carbon with sufficient valency but not on the ω carbon and selectedfrom R₇, R₉, —OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —NO₂, —C(O)NR₁₀R₁₀, —CN,—NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1substituent selected from R₂₀ and further having 0-3 substituentsindependently selected from F, Cl, Br, or I;

[0745] Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms;

[0746] Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbonatoms and having 1-4 substituents independently selected from F, or Cl;

[0747] Substituted cycloalkyl is a cyclic moiety having from 3-6 carbonatoms and having 0-3 substituents independently selected from F, or Cl,and further having 1 substituent selected from R₇, R₉, —OR₁₀, —SR₁₀,—NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, —NO₂, phenyl, or phenyl having 1 substituent selectedfrom R₂₀ and further having 0-3 substituents independently selected fromF, Cl, Br, or I;

[0748] Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2atoms within the ring being —S—, —N(R₁₉)—, or —O—;

[0749] Halogenated heterocycloalkyl is a cyclic moiety having from 4-7atoms with 1-2 atoms within the ring being —S—, —N(R₁₉)—, or —O—, andhaving 1-4 substituents independently selected from F, or Cl;

[0750] Substituted heterocycloalkyl is a cyclic moiety having from 4-7atoms with 1-2 atoms within the ring being —S—, —N(R₁₉)—, or —O— andhaving 0-3 substituents independently selected from F, or Cl, andfurther having 1 substituent selected from R₇, R₉, —OR₁₀, —SR₁₀,—NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀, —NO₂,—S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituentselected from R₂₀ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I;

[0751] Lactam heterocycloalkyl is a cyclic moiety having from 4-7 atomswith one atom being only nitrogen with the bond to the lactamheterocycloalkyl thru said atom being only nitrogen and having a ═O on acarbon adjacent to said nitrogen, and having up to 1 additional ringatom being oxygen, sulfur, or nitrogen and further having 0-2substituents selected from F, Cl, Br, I, or R₁₅ where valency allows;

[0752] Aryl is phenyl, substituted phenyl, naphthyl, or substitutednaphthyl;

[0753] Substituted phenyl is a phenyl either having 1-4 substituentsindependently selected from F, Cl, Br, or I, or having 1 substituentselected from R₁₂ and 0-3 substituents independently selected from F,Cl, Br, or I;

[0754] Substituted naphthyl is a naphthalene moiety either having 1-4substituents independently selected from F, Cl, Br, or I, or having 1substituent selected from R₁₂ and 0-3 substituents independentlyselected from F, Cl, Br, or I, where the substitution can beindependently on either the same ring or different rings of saidnaphthalene moiety;

[0755] R₆ is H, F, Cl, CN, alkyl, substituted alkyl, cycloalkyl,halogenated alkyl, and aryl;

[0756] R₇ is 5-membered heteroaromatic mono-cyclic moieties containingwithin the ring 1-3 heteroatoms independently selected from the groupconsisting of —O—, ═N—, —N(R₁₉)—, and —S—, and having 0-1 substituentselected from R₂₀ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I, or R₇ is a 9-membered fused-ring moietyhaving a 6-membered ring fused to a 5-membered ring and having theformula

[0757] wherein A₁ is O, S, or NR₁₉,

[0758] wherein A is CR₁₈ or N, A₂ and A₃ are independently selected fromCR₁₈, C(R₁₈)₂, O, S, N, or NR₁₉, provided that both A₂ and A₃ are notsimultaneously O, simultaneously S, or simultaneously O and S, or

[0759] wherein A is CR₁₈ or N, A₂ and A₃ are independently selected fromCR₁₈, C(R₁₈)₂, O, S, N, or NR₁₉, each 9-membered fused-ring moietyhaving 0-1 substituent selected from R₂₀ and further having 0-3substituent(s) independently selected from F, Cl, Br, or I, and having abond directly or indirectly attached to the core molecule where valencyallows in either the 6-membered or the 5-membered ring of the fused-ringmoiety;

[0760] Each R₈ is independently H, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl;

[0761] R₉ is 6-membered heteroaromatic mono-cyclic moieties containingwithin the ring 1-3 heteroatoms selected from ═N— and having 0-1substituent selected from R₂₀ and 0-3 substituent(s) independentlyselected from F, Cl, Br, or I, or R₉ is 10-membered heteroaromaticbi-cyclic moieties containing within one or both rings 1-3 heteroatomsselected from ═N—, including, but not limited to, quinolinyl orisoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituentselected from R₂₀ and 0-3 substituent(s) independently selected from F,Cl, Br, or I, and having a bond directly or indirectly attached to thecore molecule where valency allows;

[0762] Each R₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl,alkyl substituted with 1 substituent selected from R₁₃, cycloalkylsubstituted with 1 substituent selected from R₁₃, heterocycloalkylsubstituted with 1 substituent selected from R₁₃, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, R₇, R₉, orphenyl having 1 substituent selected from R₂₀ and further having 0-3substituents independently selected from F, Cl, Br, or I;

[0763] Each R₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, or halogenatedheterocycloalkyl;

[0764] R₁₂ is —OR₁₁, —SR₁₁, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl,R₇, R₉, —NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,—S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, or phenyl having 0-1 substituent selectedfrom R₂₀ and further having 0-3 substituents independently selected fromF, Cl, Br, or I;

[0765] R₁₃ is —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN,—NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, —CF₃, or —NO₂;

[0766] Each R₁₄ is independently H, alkyl, halogenated alkyl, limitedsubstituted alkyl, cycloalkyl, halogenated cycloalkyl, substitutedcycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, orsubstituted heterocycloalkyl;

[0767] R₁₅ is alkyl, substituted alkyl, halogenated alkyl, —OR₁₁, —CN,NO₂, —NR₁₀R₁₀;

[0768] R₁₆ is —OR₁₇, —NR₁₇R₁₇, —NR₁₇C(O)R₁₇, —NR₁₇S(O)₂R₁₇,—N(R₁₇)C(O)NR₁₇R₁₇, —NR₁₇C(O)OR₁₇;

[0769] R₁₇ is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedheterocycloalkyl, phenyl, phenyl having 1-4 substituents independentlyselected from F, Cl, Br, I and R₁₅, naphthyl, or naphthyl having 1-4substituents independently selected from F, Cl, Br, I and R₁₅;

[0770] Each R₁₈ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl,—OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,—S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, F, Cl, Br, or I, or a bond directly orindirectly attached to the core molecule, provided that there is onlyone said bond to the core molecule within the 9-membered fused-ringmoiety, further provided that the fused-ring moiety has 0-1 substituentselected from alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁,—NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,—S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁, and further provided that thefused-ring moiety has 0-3 substituent(s) selected from F, Cl, Br, or I;

[0771] R₁₉ is H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl,—SO₂R₈, or phenyl having 1 substituent selected from R₂₀ and furtherhaving 0-3 substituents independently selected from F, Cl, Br, or I;

[0772] R₂₀ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, —OR₁₁, —SR₁₁,—NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁,—NR₁₁S(O)₂R₁₁, —NO₂, alkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R₁₃, cycloalkyl substitutedwith 1-4 substituent(s) independently selected from F. Cl, Br, I, orR₁₃, or heterocycloalkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R₁₃;

[0773] or pharmaceutical composition, pharmaceutically acceptable salt,racemic mixture, or pure enantiomer thereof useful to treat any one ormore or combination of the following: cognitive and attention deficitsymptoms of Alzheimer's, neurodegeneration associated with diseases suchas Alzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problems ingeneral and associated with brain tumors, AIDS dementia complex,dementia associated with Down's syndrome, dementia associated with LewyBodies, Huntington's disease, Parkinson's disease, tardive dyskinesia,Pick's disease, dysregulation of food intake including bulemia andanorexia nervosa, withdrawal symptoms associated with smoking cessationand dependant drug cessation, Gilles de la Tourette's Syndrome,age-related macular degeneration, glaucoma, neurodegeneration associatedwith glaucoma, or symptoms associated with pain.

[0774] In another aspect, the invention includes methods of treating amammal suffering from schizophrenia or psychosis by administeringcompounds of Formula I in conjunction with antipsychotic drugs. Thecompounds of Formula I and the antipsychotic drugs can be administeredsimultaneously or at separate intervals. When administeredsimultaneously the compounds of Formula I and the antipsychotic drugscan be incorporated into a single pharmaceutical composition.Alternatively, two separate compositions, i.e., one containing compoundsof Formula I and the other containing antipsychotic drugs, can beadministered simultaneously.

[0775] The present invention also includes the compounds of the presentinvention, pharmaceutical compositions containing the active compounds,and methods to treat the identified diseases.

[0776] Non-inclusive examples of heteroaryl compounds that fall withinthe definition of R₇ and R₉ include, but are not limited to, thienyl,benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl,imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl,pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl,isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl,quinoxalinyl, naphthridinyl, and furopyridinyl.

[0777] Non-inclusive examples of heterocycloalkyl include, but are notlimited to, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino,piperidino, piperazine, azetidino, azetidinono, oxindolo,dihydroimidazolo, and pyrrolidinono

[0778] Some of the amines described herein require the use of anamine-protecting group to ensure functionalization of the desirednitrogen. One of ordinary skill in the art would appreciate where,within the synthetic scheme to use said protecting group. Aminoprotecting group includes, but is not limited to, carbobenzyloxy (CBz),tert butoxy carbonyl (BOC) and the like. Examples of other suitableamino protecting groups are known to person skilled in the art and canbe found in “Protective Groups in Organic synthesis,” 3rd Edition,authored by Theodora Greene and Peter Wuts.

[0779] Abbreviations which are well known to one of ordinary skill inthe art may be used (e.g., “Ph” for phenyl, “Me” for methyl, “Et” forethyl, “h” for hour or hours, “min” for minute or minutes, and “rt” or“RT” for room temperature).

[0780] All temperatures are in degrees Centigrade.

[0781] Room temperature is within the range of 15-25 degrees Celsius.

[0782] AChR refers to acetylcholine receptor.

[0783] Pre-senile dementia is also known as mild cognitive impairment.

[0784] nAChR refers to nicotinic acetylcholine receptor.

[0785] 5HT₃R refers to the serotonin-type 3 receptor.

[0786] α-btx refers to α-bungarotoxin.

[0787] FLIPR refers to a device marketed by Molecular Devices, Inc.designed to precisely measure cellular fluorescence in a high throughputwhole-cell assay. (Schroeder et. al., J. Biomolecular Screening, 1(2), p75-80, 1996).

[0788] TLC refers to thin-layer chromatography.

[0789] HPLC refers to high pressure liquid chromatography.

[0790] MeOH refers to methanol.

[0791] EtOH refers to ethanol.

[0792] IPA refers to isopropyl alcohol.

[0793] THF refers to tetrahydrofuran.

[0794] DMSO refers to dimethylsulfoxide.

[0795] DMF refers to dimethylformamide.

[0796] EtOAc refers to ethyl acetate.

[0797] Na₂SO₄ refers to anhydrous sodium sulfate.

[0798] K₂CO₃ refers to potassium carbonate.

[0799] MgSO₄ refers to anhydrous magnesium sulfate.

[0800] TMS refers to tetramethylsilane.

[0801] TEA refers to triethylamine.

[0802] DIEA refers to N,N-diisopropylethylamine.

[0803] MLA refers to methyllycaconitine.

[0804] Ether refers to diethyl ether.

[0805] HATU refers toO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

[0806] DPPA refers to diphenylphosphoryl azide.

[0807] 50% saturated 1:1 NaCl/NaHCO₃ means a solution made by making asolution of 1:1 saturated NaCl/NaHCO₃ and adding an equal volume ofwater.

[0808] CH₃SO₂Cl refers to methanesulfonyl chloride.

[0809] Halogen is F, Cl, Br, or I.

[0810] The carbon atom content of various hydrocarbon-containingmoieties is indicated by a prefix designating the minimum and maximumnumber of carbon atoms in the moiety, i.e., the prefix C_(i-j) indicatesa moiety of the integer “i” to the integer “j” carbon atoms, inclusive.Thus, for example, C₁₋₆ alkyl refers to alkyl of one to six carbonatoms.

[0811] The ω carbon is determined by counting the longest carbon chainof the alkyl-type moiety with the C-1 carbon being the carbon attachedto W of the core molecule and the ω carbon being the carbon furthest,e.g., separated by the greatest number of carbon atoms in the chain,from said C-1 carbon.

[0812] The core molecule is the azabicyclo-(carboxamide-type moiety)-W:

[0813] Therefore, when determining the ω carbon, the C-1 carbon will bethe carbon attached to W of the core molecule and the ω carbon will bethe carbon furthest from said C-1 carbon.

[0814] One of the most conventionally accepted ways of naming thecompound pictured below is 5-(2-aminophenyl)-N-[1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide, but for oneordinarily skilled in the art, the following name also describes thesame compound, N-[1-azabicyclo[2.2.1]hept-3-yl]-5-(2-aminophenyl)-thiophene-2-carboxamide:

[0815] The two are used interchangeably in this patent.

[0816] Mammal denotes human and other mammals.

[0817] Brine refers to an aqueous saturated sodium chloride solution.

[0818] Equ means molar equivalents.

[0819] IR refers to infrared spectroscopy.

[0820] Lv refers to leaving groups within a molecule, including Cl, OMe,OEt, or mixed anhydride.

[0821] Parr refers to the name of the company who sells the jars usedfor conducting reactions under pressure.

[0822] PSI means pound per square inch.

[0823] NMR refers to nuclear (proton) magnetic resonance spectroscopy,chemical shifts are reported in ppm (δ) downfield from TMS.

[0824] MS refers to mass spectrometry expressed as m/e or mass/chargeunit. HRMS refers to high resolution mass spectrometry expressed as m/eor mass/charge unit. [M+H]⁺ refers to an ion composed of the parent plusa proton. [M−H]⁻ refers to an ion composed of the parent minus a proton.[M+Na]⁺ refers to an ion composed of the parent plus a sodium ion.[M+K]⁺ refers to an ion composed of the parent plus a potassium ion. EIrefers to electron impact. ESI refers to electrospray ionization. CIrefers to chemical ionization. FAB refers to fast atom bombardment.

[0825] Compounds of the present invention may be in the form ofpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalts” refers to salts prepared from pharmaceutically acceptablenon-toxic bases including inorganic bases and organic bases, and saltsprepared from inorganic acids, and organic acids. Salts derived frominorganic bases include aluminum, ammonium, calcium, ferric, ferrous,lithium, magnesium, potassium, sodium, zinc, and the like. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, and the like. Salts derived from inorganic acids includesalts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, phosphorous acid and the like. Salts derived frompharmaceutically acceptable organic non-toxic acids include salts ofC₁₋₆ alkyl carboxylic acids, di-carboxylic acids, and tri-carboxylicacids such as acetic acid, propionic acid, fumaric acid, succinic acid,tartaric acid, maleic acid, adipic acid, and citric acid, and aryl andalkyl sulfonic acids such as toluene sulfonic acids and the like.

[0826] By the term “effective amount” of a compound as provided hereinis meant a nontoxic but sufficient amount of the compound(s) to providethe desired effect. As pointed out below, the exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the disease that is beingtreated, the particular compound(s) used, the mode of administration,and the like. Thus, it is not possible to specify an exact “effectiveamount.” However, an appropriate effective amount may be determined byone of ordinary skill in the art using only routine experimentation.

[0827] The amount of therapeutically effective compound(s) that isadministered and the dosage regimen for treating a disease conditionwith the compounds and/or compositions of this invention depends on avariety of factors, including the age, weight, sex and medical conditionof the subject, the severity of the disease, the route and frequency ofadministration, and the particular compound(s) employed, and thus mayvary widely. The compositions contain well know carriers and excipientsin addition to a therapeutically effective amount of compounds ofFormula I. The pharmaceutical compositions may contain active ingredientin the range of about 0.001-100 mg/kg/day for an adult, preferably inthe range of about 0.1-50 mg/kg/day for an adult. A total daily dose ofabout 1-1000 mg of active ingredient may be appropriate for an adult.The daily dose can be administered in one to four doses per day.

[0828] In addition to the compound(s) of Formula I, the composition fortherapeutic use may also comprise one or more non-toxic,pharmaceutically acceptable carrier materials or excipients. The term“carrier” material or “excipient” herein means any substance, not itselfa therapeutic agent, used as a carrier and/or diluent and/or adjuvant,or vehicle for delivery of a therapeutic agent to a subject or added toa pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improve appearance of the composition.Acceptable excipients include lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropyl-methyl cellulose, orother methods known to those skilled in the art. For oraladministration, the pharmaceutical composition may be in the form of,for example, a tablet, capsule, suspension or liquid. If desired, otheractive ingredients may be included in the composition.

[0829] In addition to the oral dosing, noted above, the compositions ofthe present invention may be administered by any suitable route, in theform of a pharmaceutical composition adapted to such a route, and in adose effective for the treatment intended. The compositions may, forexample, be administered parenterally, e.g., intravascularly,intraperitoneally, subcutaneously, or intramuscularly. For parenteraladministration, saline solution, dextrose solution, or water may be usedas a suitable carrier. Formulations for parenteral administration may bein the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions may beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. The compounds may be dissolved in water, polyethyleneglycol, propylene glycol, EtOH, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art.

[0830] The serotonin type 3 receptor (5HT₃R) is a member of asuperfamily of ligand-gated ion channels, which includes the muscle andneuronal nAChR, the glycine receptor, and the γ-aminobutyric acid type Areceptor. Like the other members of this receptor superfamily, the 5HT₃Rexhibits a large degree of sequence homology with α7 nAChR butfunctionally the two ligand-gated ion channels are very different. Forexample, α7 nAChR is rapidly inactivated, is highly permeable to calciumand is activated by acetylcholine and nicotine. On the other hand, 5HT₃Ris inactivated slowly, is relatively impermeable to calcium and isactivated by serotonin. These experiments suggest that the α7 nAChR and5HT₃R proteins have some degree of homology, but function verydifferently. Indeed the pharmacology of the channels is very different.For example, Ondansetron, a highly selective 5HT₃R antagonist, haslittle activity at the α7 nAChR. The converse is also true. For example,GTS-21, a highly selective α7 nAChR agonist, has little activity at the5HT₃R.

[0831] α7 nAChR is a ligand-gated Ca⁺⁺ channel formed by a homopentamerof α7 subunits. Previous studies have established that α-bungarotoxin(α-btx) binds selectively to this homopetameric, α7 nAChR subtype, andthat α7 nAChR has a high affinity binding site for both α-btx andmethyllycaconitine (MLA). α7 nAChR is expressed at high levels in thehippocampus, ventral tegmental area and ascending cholinergicprojections from nucleus basilis to thalamocortical areas. α7 nAChRagonists increase neurotransmitter release, and increase cognition,arousal, attention, learning and memory.

[0832] Data from human and animal pharmacological studies establish thatnicotinic cholinergic neuronal pathways control many important aspectsof cognitive function including attention, learning and memory (Levin,E. D., Psychopharmacology, 108:417-31, 1992; Levin, E. D. and Simon B.B., Psychopharmacology, 138:217-30, 1998). For example, it is well knownthat nicotine increases cognition and attention in humans. ABT-418, acompound that activates α4β2 and α7 nAChR, improves cognition andattention in clinical trials of Alzheimer's disease andattention-deficit disorders (Potter, A. et. al., Psychopharmacology(Berl)., 142(4):334-42, March 1999; Wilens, T. E. et. al., Am. J.Psychiatry, 156(12):1931-7, December 1999). It is also clear thatnicotine and selective but weak α7 nAChR agonists increase cognition andattention in rodents and non-human primates.

[0833] Schizophrenia is a complex multifactorial illness caused bygenetic and non-genetic risk factors that produce a constellation ofpositive and negative symptoms. The positive symptoms include delusionsand hallucinations and the negative symptoms include deficits in affect,attention, cognition and information processing. No single biologicalelement has emerged as a dominant pathogenic factor in this disease.Indeed, it is likely that schizophrenia is a syndrome that is producedby the combination of many low penetrance risk factors. Pharmacologicalstudies established that dopamine receptor antagonists are efficaciousin treating the overt psychotic features (positive symptoms) ofschizophrenia such as hallucinations and delusions. Clozapine, an“atypical” antipsychotic drug, is novel because it is effective intreating both the positive and some of the negative symptoms of thisdisease. Clozapine's utility as a drug is greatly limited becausecontinued use leads to an increased risk of agranulocytosis and seizure.No other antipsychotic drug is effective in treating the negativesymptoms of schizophrenia. This is significant because the restorationof cognitive functioning is the best predictor of a successful clinicaland functional outcome of schizophrenic patients (Green, M. F., Am JPsychiatry, 153:321-30, 1996). By extension, it is clear that betterdrugs are needed to treat the cognitive disorders of schizophrenia inorder to restore a better state of mental health to patients with thisdisorder.

[0834] One aspect of the cognitive deficit of schizophrenia can bemeasured by using the auditory event-related potential (P50) test ofsensory gating. In this test, electroencepholographic (EEG) recordingsof neuronal activity of the hippocampus are used to measure thesubject's response to a series of auditory “clicks” (Adler, L. E. et.al., Biol. Psychiatry, 46:8-18, 1999). Normal individuals respond to thefirst click with greater degree than to the second click. In general,schizophrenics and schizotypal patients respond to both clicks nearlythe same (Cullum, C. M. et. al., Schizophr. Res., 10:131-41, 1993).These data reflect a schizophrenic's inability to “filter” or ignoreunimportant information. The sensory gating deficit appears to be one ofthe key pathological features of this disease (Cadenhead, K. S. et. al.,Am. J. Psychiatry, 157:55-9, 2000). Multiple studies show that nicotinenormalizes the sensory deficit of schizophrenia (Adler, L. E. et. al.,Am. J. Psychiatry, 150:1856-61, 1993). Pharmacological studies indicatethat nicotine's effect on sensory gating is via the α7 nAChR (Adler, L.E. et. al., Schizophr. Bull., 24:189-202, 1998). Indeed, the biochemicaldata indicate that schizophrenics have 50% fewer of α7 nAChR receptorsin the hippocampus, thus giving a rationale to partial loss of α7 nAChRfunctionality (Freedman, R. et. al., Biol. Psychiatry, 38:22-33, 1995).Interestingly, genetic data indicate that a polymorphism in the promoterregion of the α7 nAChR gene is strongly associated with the sensorygating deficit in schizophrenia (Freedman, R. et. al., Proc. Nat'l Acad.Sci. USA, 94(2):587-92, 1997; Myles-Worsley, M. et. al., Am. J. Med.Genet, 88(5):544-50, 1999). To date, no mutation in the coding region ofthe α7 nAChR has been identified. Thus, schizophrenics express the sameα7 nAChR as non-schizophrenics.

[0835] Selective α7 nAChR agonists may be found using a functional assayon FLIPR (see WO 00/73431 A2). FLIPR is designed to read the fluorescentsignal from each well of a 96 or 384 well plate as fast as twice asecond for up to 30 minutes. This assay may be used to accuratelymeasure the functional pharmacology of α7 nAChR and 5HT₃R. To conductsuch an assay, one uses cell lines that expressed functional forms ofthe α7 nAChR using the α7/5-HT₃ channel as the drug target and celllines that expressed functional 5HT₃R. In both cases, the ligand-gatedion channel was expressed in SH-EP1 cells. Both ion channels can producerobust signal in the FLIPR assay.

[0836] The compounds of the present invention are α7 nAChR agonists andmay be used to treat a wide variety of diseases. For example, they maybe used in treating schizophrenia, or psychosis.

[0837] Schizophrenia is a disease having multiple aspects. Currentlyavailable drugs are generally aimed at controlling the positive aspectsof schizophrenia, such as delusions. One drug, Clozapine, is aimed at abroader spectrum of symptoms associated with schizophrenia. This drughas many side effects and is thus not suitable for many patients. Thus,there is a need for a drug to treat the cognitive and attention deficitsassociated with schizophrenia. Similarly, there is a need for a drug totreat the cognitive and attention deficits associated withschizoaffective disorders, or similar symptoms found in the relatives ofschizophrenic patients.

[0838] Psychosis is a mental disorder characterized by gross impairmentin the patient's perception of reality. The patient may suffer fromdelusions, and hallucinations, and may be incoherent in speech. Hisbehavior may be agitated and is often incomprehensible to those aroundhim. In the past, the term psychosis has been applied to many conditionsthat do not meet the stricter definition given above. For example, mooddisorders were named as psychoses.

[0839] There are a variety of antipsychotic drugs. The conventionalantipsychotic drugs include Chlorpromazine, Fluphenazine, Haloperidol,Loxapine, Mesoridazine, Molindone, Perphenazine, Pimozide, Thioridazine,Thiothixene, and Trifluoperazine. These drugs all have an affinity forthe dopamine 2 receptor.

[0840] These conventional antipsychotic drugs have several side effects,including sedation, weight gain, tremors, elevated prolactin levels,akathisia (motor restlessness), dystonia and muscle stiffness. Thesedrugs may also cause tardive dyskinesia. Unfortunately, only about 70%of patients with schizophrenia respond to conventional antipsychoticdrugs. For these patients, atypical antipsychotic drugs are available.

[0841] Atypical antipsychotic drugs generally are able to alleviatepositive symptoms of psychosis while also improving negative symptoms ofthe psychosis to a greater degree than conventional antipsychotics.These drugs may improve neurocognitive deficits. Extrapyramidal (motor)side effects are not as likely to occur with the atypical antipsychoticdrugs, and thus, these atypical antipsychotic drugs have a lower risk ofproducing tardive dyskinesia. Finally these atypical antipsychotic drugscause little or no elevation of prolactin. Unfortunately, these drugsare not free of side effects. Although these drugs each producedifferent side effects, as a group the side effects include:agranulocytosis; increased risk of seizures, weight gain, somnolence,dizziness, tachycardia, decreased ejaculatory volume, and mildprolongation of QTc interval.

[0842] In a combination therapy to treat multiple symptoms of diseasessuch as schizophrenia, the compounds of Formula I and the anti-psychoticdrugs can be administered simultaneously or at separate intervals. Whenadministered simultaneously the compounds of Formula I and theanti-psychotic drugs can be incorporated into a single pharmaceuticalcomposition, e.g., a pharmaceutical combination therapy composition.Alternatively, two separate compositions, i.e., one containing compoundsof Formula I and the other containing anti-psychotic drugs, can beadministered simultaneously. Examples of anti-psychotic drugs, inaddition to those listed above, include, but are not limited to,Thorazine, Mellaril, Trilafon, Navane, Stelazine, Permitil, Prolixin,Risperdal, Zyprexa, Seroquel, ZELDOX, Acetophenazine, Carphenazine,Chlorprothixene, Droperidol, Loxapine, Mesoridazine, Molindone,Ondansetron, Pimozide, Prochlorperazine, and Promazine.

[0843] A pharmaceutical combination therapy composition can includetherapeutically effective amounts of the compounds of Formula I, notedabove, and a therapeutically effective amount of anti-psychotic drugs.These compositions may be formulated with common excipients, diluents orcarriers, and compressed into tablets, or formulated elixirs orsolutions for convenient oral administration or administered byintramuscular intravenous routes. The compounds can be administeredrectally, topically, orally, sublingually, or parenterally and maybeformulated as sustained relief dosage forms and the like.

[0844] When separately administered, therapeutically effective amountsof compositions containing compounds of Formula I and anti-psychoticdrugs are administered on a different schedule. One may be administeredbefore the other as long as the time between the two administrationsfalls within a therapeutically effective interval. A therapeuticallyeffective interval is a period of time beginning when one of either (a)the compounds of Formula I, or (b) the anti-psychotic drugs isadministered to a human and ending at the limit of the beneficial effectin the treatment of schizophrenia or psychosis of the combination of (a)and (b). The methods of administration of the compounds of Formula I andthe anti-psychotic drugs may vary. Thus, either agent or both agents maybe administered rectally, topically, orally, sublingually, orparenterally.

[0845] As discussed, the compounds of the present invention are α7 nAChRagonists. Therefore, as another aspect of the present invention, thecompounds of the present invention may be used to treat a variety ofdiseases including cognitive and attention deficit symptoms ofAlzheimer's Disease, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (also known as mild cognitiveimpairment), and senile dementia.

[0846] Alzheimer's disease has many aspects, including cognitive andattention deficits. Currently, these deficits are treated withcholinesterase inhibitors. These inhibitors slow the break down ofacetylcholine, and thereby provide a general nonspecific increase in theactivity of the cholinergic nervous system. Since the drugs arenonspecific, they have a wide variety of side effects. Thus, there is aneed for a drug that stimulates a portion of the cholinergic pathwaysand thereby provides improvement in the cognitive and attention deficitsassociated with Alzheimer's disease without the side effects created bynonspecific stimulation of the cholinergic pathways.

[0847] Neurodegeneration is a common problem associated with diseasessuch as Alzheimer's disease. While the current drugs treat some of thesymptoms of this disease, they do not control the underlying pathologyof the disease. Accordingly, it would be desirable to provide a drugthat can slow the progress of Alzheimer's disease.

[0848] Pre-senile dementia (mild cognitive impairment) concerns memoryimpairment rather than attention deficit problems and otherwiseunimpaired cognitive functioning. Mild cognitive impairment isdistinguished from senile dementia in that mild cognitive impairmentinvolves a more persistent and troublesome problem of memory loss forthe age of the patient. There currently is no medication specificallyidentified for treatment of mild cognitive impairment, due somewhat tothe newness of identifying the disease. Therefore, there is a need for adrug to treat the memory problems associated with mild cognitiveimpairment.

[0849] Senile dementia is not a single disease state. However, theconditions classified under this name frequently include cognitive andattention deficits. Generally, these deficits are not treated.Accordingly, there is a need for a drug that provides improvement in thecognitive and attention deficits associated with senile dementia.

[0850] As discussed, the compounds of the present invention are α7 nAChRagonists. Therefore, yet other diseases to be treated with compounds ofthe present invention include treating the cognitive and attentiondeficits as well as the neurodegeneration associated with any one ormore or combination of the following: attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problemsassociated with brain tumors, AIDS dementia complex, dementia associatedwith Down's syndrome, dementia associated with Lewy Bodies, Huntington'sdisease, Parkinson's disease, tardive dyskinesia, Pick's disease,dysregulation of food intake including bulemia and anorexia nervosa,withdrawal symptoms associated with smoking cessation and dependant drugcessation, Gilles de la Tourette's Syndrome, age-related maculardegeneration, glaucoma, neurodegeneration associated with glaucoma, orsymptoms associated with pain.

[0851] Attention deficit disorder is generally treated withmethylphenidate, an amphetamine-like molecule that has some potentialfor abuse. Accordingly, it would be desirable to provide a drug thattreats attention deficit disorder while having fewer side effects thanthe currently used drug.

[0852] Attention deficit hyperactivity disorder, otherwise known asADHD, is a neurobehavioral disorder affecting 3-5% of all Americanchildren. ADHD concerns cognitive alone or both cognitive and behavioralactions by interfering with a person's ability to stay on a task and toexercise age-appropriate inhibition. Several types of ADHD exist: apredominantly inattentive subtype, a predominantly hyperactive-impulsivesubtype, and a combined subtype. Treatment may include medications suchas methylphenidate, dextroamphetamine, or pemoline, which act todecrease impulsivity and hyperactivity and to increase attention. No“cure” for ADHD currently exists. Children with the disorder seldomoutgrow it; therefore, there is a need for appropriate medicaments.

[0853] Depression is a mood disorder of varying lengths of normallyseveral months to more than two years and of varying degrees of feelingsinvolving sadness, despair, and discouragement. The heterocyclicantidepressants (HCA's) are currently the largest class ofantidepressants, but monoamine oxidase inhibitors (MAOI's) are used inparticular types of depression. Common side effects from HCA's aresedation and weight gain. In elderly patients with organic braindisease, the side effects from HCA's can also include seizures andbehavioral symptoms. The main side effects from using MAOI's occur fromdietary and drug interactions. Therefore, agents with fewer side effectswould be useful.

[0854] Anxiety disorders (disorders with prominent anxiety or phobicavoidance), represent an area of umet medical needs in the treatment ofpsychiatric illness. See Diagnostic & Statistical Manual of MentalDisorders, IV (1994), pp 393-394, for various disease forms of anxiety.

[0855] General anxiety disorder (GAD) occurs when a person worries aboutthings such as family, health, or work when there is no reason to worryand is unable not to worry. About 3 to 4% of the U.S. population has GADduring the course of a year. GAD most often strikes people in childhoodor adolescence, but can begin in adulthood, too. It affects women moreoften than men. Currently, treatment involves cognitive-behavioraltherapy, relaxation techniques, and biofeedback to control muscletension and medications such as benzodiazepines, imipramine, andbuspirone. These drugs are effective but all have side-effectliabilities. Therefore, there is a need of a pharmaceutical agent toaddress the symptoms with fewer side effects.

[0856] Anxiety also includes post-traumatic stress disorder (PTSD),which is a form of anxiety triggered by memories of a traumatic eventthat directly affected the patient or that the patient may havewitnessed. The disorder commonly affects survivors of traumatic eventsincluding sexual assault, physical assault, war, torture, naturaldisasters, an automobile accident, an airplane crash, a hostagesituation, or a death camp. The affliction also can affect rescueworkers at an airplane crash or a mass shooting, someone who witnessed atragic accident or someone who has unexpectedly lost a loved one.Treatment for PTSD includes cognitive-behavioral therapy, grouppsychotherapy, and medications such as Clonazepam, Lorazepam andselective serotonin-reuptake inhibitors such as Fluoxetine, Sertraline,Paroxetine, Citalopram and Fluvoxamine. These medications help controlanxiety as well as depression. Various forms of exposure therapy (suchas systemic desensitization and imaginal flooding) have all been usedwith PTSD patients. Exposure treatment for PTSD involves repeatedreliving of the trauma, under controlled conditions, with the aim offacilitating the processing of the trauma. Therefore, there is a needfor better pharmaceutical agents to treat post traumatic stressdisorder.

[0857] Mood and affective disorders fall within a large group ofdiseases, including monopolar depression and bi-polar mood disorder.These diseases are treated with three major classes of compounds. Thefirst group is the heterocyclic antidepressant (HCA's). This groupincludes the well-known tricyclic antidepressants. The second group ofcompounds used to treat mood disorders is the monoamine oxidaseinhibitors (MAOI's) that are used in particular types of diseases. Thethird drug is lithium. Common side effects from HCA's are sedation andweight gain. In elderly patients with organic brain disease, the sideeffects of HCA's can also include seizures and behavioral symptoms. Themain side effects from using MAOI's occur from dietary and druginteractions. Benign side effects from the use of lithium include, butare not limited to, weight gain, nausea, diarrhea, polyuria, polydipsia,and tremor. Toxic side effects from lithium can include persistentheadache, mental confusion, and may reach seizures and cardiacarrhythmias. Therefore, agents with less side effects or interactionswith food or other medications would be useful.

[0858] Borderline personality disorder, although not as well known asbipolar disorder, is more common. People having borderline personalitydisorder suffer from a disorder of emotion regulation. Pharmaceuticalagents are used to treat specific symptoms, such as depression orthinking distortions.

[0859] Acquired immune deficiency syndrome (AIDS) results from aninfection with the human immunodeficiency virus (HIV). This virusattacks selected cells and impairs the proper function of the immune,nervous, and other systems. HIV infection can cause other problems suchas, but not limited to, difficulties in thinking, otherwise known asAIDS dementia complex. Therefore, there is a need to drugs to relievethe confusion and mental decline of persons with AIDS.

[0860] Amyotrophic lateral sclerosis, also known as Lou Gehrig'sdisease, belongs to a class of disorders known as motor neuron diseaseswherein specific nerve cells in the brain and spinal cord graduallydegenerate to negatively affect the control of voluntary movement.Currently, there is no cure for amyotrophic lateral sclerosis althoughpatients may receive treatment from some of their symptoms and althoughRiluzole has been shown to prolong the survival of patients. Therefore,there is a need for a pharmaceutical agent to treat this disease.

[0861] Traumatic brain injury occurs when the brain is damaged from asudden physical assault on the head. Symptoms of the traumatic braininjury include confusion and other cognitive problems. Therefore, thereis a need to address the symptoms of confusion and other cognitiveproblems.

[0862] Brain tumors are abnormal growths of tissue found inside of theskull. Symptoms of brain tumors include behavioral and cognitiveproblems. Surgery, radiation, and chemotherapy are used to treat thetumor, but other agents are necessary to address associated symptoms.Therefore, there is a need to address the symptoms of behavioral andcognitive problems.

[0863] Persons with Down's syndrome have in all or at least some oftheir cells an extra, critical portion of the number 21 chromosome.Adults who have Down's syndrome are known to be at risk forAlzheimer-type dementia. Currently, there is no proven treatment forDown's syndrome. Therefore, there is a need to address the dementiaassociated with Down's syndrome.

[0864] Genetically programmed degeneration of neurons in certain areasof the brain cause Huntington's disease. Early symptoms of Huntington'sdisease include mood swings, or trouble learning new things orremembering a fact. Most drugs used to treat the symptoms ofHuntington's disease have side effects such as fatigue, restlessness, orhyperexcitability. Currently, there is no treatment to stop or reversethe progression of Huntington's disease. Therefore, there is a need of apharmaceutical agent to address the symptoms with fewer side effects.

[0865] Dementia with Lewy Bodies is a neurodegenerative disorderinvolving abnormal structures known as Lewy bodies found in certainareas of the brain. Symptoms of dementia with Lewy bodies include, butare not limited to, fluctuating cognitive impairment with episodicdelirium. Currently, treatment concerns addressing the parkinsonian andpsychiatric symptoms. However, medicine to control tremors or loss ofmuscle movement may actually accentuate the underlying disease ofdementia with Lewy bodies. Therefore, there is a need of apharmaceutical agent to treat dementia with Lewy bodies.

[0866] Parkinson's disease is a neurological disorder characterized bytremor, hypokinesia, and muscular rigidity. Currently, there is notreatment to stop the progression of the disease. Therefore, there is aneed of a pharmaceutical agent to address Parkinson's.

[0867] Tardive dyskinesia is associated with the use of conventionalantipsychotic drugs. This disease is characterized by involuntarymovements most often manifested by puckering of the lips and tongueand/or writhing of the arms or legs. The incidence of tardive dyskinesiais about 5% per year of drug exposure among patients taking conventionalantipsychotic drugs. In about 2% of persons with the disease, tardivedyskinesia is severely disfiguring. Currently, there is no generalizedtreatment for tardive dyskinesia. Furthermore, the removal of theeffect-causing drugs is not always an option due to underlying problems.Therefore, there is a need for a pharmaceutical agent to address thesymptoms of tardive dyskinesia.

[0868] Pick's disease results from a slowly progressive deterioration ofsocial skills and changes in personality with the resulting symptomsbeing impairment of intellect, memory, and language. Common symptomsinclude memory loss, lack of spontaneity, difficulty in thinking orconcentrating, and speech disturbances. Currently, there is no specifictreatment or cure for Pick's disease but some symptoms can be treatedwith cholinergic and serotonin-boosting antidepressants. In addition,antipsychotic medications may alleviate symptoms in FTD patients who areexperiencing delusions or hallucinations. Therefore, there is a need fora pharmaceutical agent to treat the progressive deterioration of socialskills and changes in personality and to address the symptoms with fewerside effects.

[0869] Dysregulation of food intake associated with eating disease,including bulemia nervosa and anorexia nervosa, involveneurophysiological pathways. Anorexia nervosa is hard to treat due topatients not entering or remaining in after entering programs.Currently, there is no effective treatment for persons suffering fromsevere anorexia nervosa. Cognitive behavioral therapy has helpedpatients suffering from bulemia nervosa; however, the response rate isonly about 50% and current treatment does not adequately addressemotional regulation. Therefore, there is a need for pharmaceuticalagents to address neurophysiological problems underlying diseases ofdysregulation of food intake.

[0870] Cigarette smoking has been recognized as a major public healthproblem for a long time. However, in spite of the public awareness ofhealth hazard, the smoking habit remains extraordinarily persistent anddifficult to break. There are many treatment methods available, and yetpeople continue to smoke. Administration of nicotine transdermally, orin a chewing gum base is common treatments. However, nicotine has alarge number of actions in the body, and thus can have many sideeffects. It is clear that there is both a need and a demand of longstanding for a convenient and relatively easy method for aiding smokersin reducing or eliminating cigarette consumption. A drug that couldselectively stimulate only certain of the nicotinic receptors would beuseful in smoke cessation programs.

[0871] Smoke cessation programs may involve oral dosing of the drug ofchoice. The drug may be in the form of tablets. However, it is preferredto administer the daily dose over the waking hours, by administration ofa series of incremental doses during the day. The preferred method ofsuch administration is a slowly dissolving lozenge, troche, or chewinggum, in which the drug is dispersed. Another drug in treating nicotineaddiction is Zyban. This is not a nicotine replacement, as are the gumand patch. Rather, this works on other areas of the brain, and itseffectiveness is to help control nicotine craving or thoughts aboutcigarette use in people trying to quit. Zyban is not very effective andeffective drugs are needed to assist smokers in their desire to stopsmoking. These drugs may be administered transdermally through the useof skin patches. In certain cases, the drugs may be administered bysubcutaneous injection, especially if sustained release formulations areused.

[0872] Drug use and dependence is a complex phenomenon, which cannot beencapsulated within a single definition. Different drugs have differenteffects, and therefore different types of dependence. Drug dependencehas two basic causes, that is, tolerance and physical dependence.Tolerance exists when the user must take progressively larger doses toproduce the effect originally achieved with smaller doses. Physicaldependence exists when the user has developed a state of physiologicadaptation to a drug, and there is a withdrawal (abstinence) syndromewhen the drug is no longer taken. A withdrawal syndrome can occur eitherwhen the drug is discontinued or when an antagonist displaces the drugfrom its binding site on cell receptors, thereby counteracting itseffect. Drug dependence does not always require physical dependence.

[0873] In addition drug dependence often involves psychologicaldependence, that is, a feeling of pleasure or satisfaction when takingthe drug. These feelings lead the user to repeat the drug experience orto avoid the displeasure of being deprived of the drug. Drugs thatproduce strong physical dependence, such as nicotine, heroin and alcoholare often abused, and the pattern of dependence is difficult to break.Drugs that produce dependence act on the CNS and generally reduceanxiety and tension; produce elation, euphoria, or other pleasurablemood changes; provide the user feelings of increased mental and physicalability; or alter sensory perception in some pleasurable manner. Amongthe drugs that are commonly abused are ethyl alcohol, opioids,anxiolytics, hypnotics, cannabis (marijuana), cocaine, amphetamines, andhallucinogens. The current treatment for drug-addicted people ofteninvolves a combination of behavioral therapies and medications.Medications, such as methadone or LAAM (levo-alpha-acetyl-methadol), areeffective in suppressing the withdrawal symptoms and drug cravingassociated with narcotic addiction, thus reducing illicit drug use andimproving the chances of the individual remaining in treatment. Theprimary medically assisted withdrawal method for narcotic addiction isto switch the patient to a comparable drug that produces milderwithdrawal symptoms, and then gradually taper off the substitutemedication. The medication used most often is methadone, taken orallyonce a day. Patients are started on the lowest dose that prevents themore severe signs of withdrawal and then the dose is gradually reduced.Substitutes can be used also for withdrawal from sedatives. Patients canbe switched to long-acting sedatives, such as diazepam or phenobarbital,which are then gradually reduced.

[0874] Gilles de la Tourette's Syndrome is an inherited neurologicaldisorder. The disorder is characterized by uncontrollable vocal soundscalled tics and involuntary movements. The symptoms generally manifestin an individual before the person is 18 years of age. The movementdisorder may begin with simple tics that progress to multiple complextics, including respiratory and vocal ones. Vocal tics may begin asgrunting or barking noises and evolve into compulsive utterances.Coprolalia (involuntary scatologic utterances) occurs in 50% ofpatients. Severe tics and coprolalia may be physically and sociallydisabling. Tics tend to be more complex than myoclonus, but less flowingthan choreic movements, from which they must be differentiated. Thepatient may voluntarily suppress them for seconds or minutes.

[0875] Currently simple tics are often treated with benzodiazepines. Forsimple and complex tics, Clonidine may be used. Long-term use ofClonidine does not cause tardive dyskinesia; its limiting adverse effectis hypotension. In more severe cases, antipsychotics, such asHaloperidol may be required, but side effects of dysphoria,parkinsonism, akathisia, and tardive dyskinesia may limit use of suchantipsychotics. There is a need for safe and effective methods fortreating this syndrome.

[0876] Age-related macular degeneration (AMD) is a common eye disease ofthe macula which is a tiny area in the retina that helps produce sharp,central vision required for “straight ahead” activities that includereading and driving. Persons with AMD lose their clear, central vision.AMD takes two forms: wet and dry. In dry AMD, there is a slow breakdownof light-sensing cells in the macula. There currently is no cure for dryAMD. In wet AMD, new, fragile blood vessels growing beneath the maculaas dry AMD worsens and these vessels often leak blood and fluid to causerapid damage to the macula quickly leading to the loss of centralvision. Laser surgery can treat some cases of wet AMD. Therefore, thereis a need of a pharmaceutical agent to address AMD.

[0877] Glaucoma is within a group of diseases occurs from an increase inintraocular pressure causing pathological changes in the optical diskand negatively affects the field of vision. Medicaments to treatglaucoma either decrease the amount of fluid entering the eye orincrease drainage of fluids from the eye in order to decreaseintraocular pressure. However, current drugs have drawbacks such as notworking over time or causing side effects so the eye-care professionalhas to either prescribe other drugs or modify the prescription of thedrug being used. There is a need for safe and effective methods fortreating problems manifesting into glaucoma.

[0878] Ischemic periods in glaucoma cause release of excitotoxic aminoacids and stimulate inducible form of nitric oxide synthase (iNOS)leading to neurodegeneration. Alpha 7 nicotinic agonists may stimulatethe release of inhibitory amino acids such as GABA which will dampenhyperexcitablity. Alpha 7 nicotinic agonists are also directlyneuroprotective on neuronal cell bodies. Thus alpha 7 nicotinic agonistshave the potential to be neuroprotective in glaucoma.

[0879] Persons afflicted with pain often have what is referred to as the“terrible triad” of suffering from the pain, resulting in sleeplessnessand sadness, all of which are hard on the afflicted individual and thatindividual's family. Pain can manifest itself in various forms,including, but not limited to, headaches of all severity, back pain,neurogenic, and pain from other ailments such as arthritis and cancerfrom its existence or from therapy to irradicate it. Pain can be eitherchronic (persistent pain for months or years) or acute (short-lived,immediate pain to inform the person of possible injury and need oftreatment). Persons suffering from pain respond differently toindividual therapies with varying degrees of success. There is a needfor safe and effective methods for treating pain.

[0880] Finally, the compounds of the present invention may be used incombination therapy with typical and atypical anti-psychotic drugs (alsocalled an anti-psychotic agent). All compounds within the presentinvention are useful for and may also be used in combination with eachother to prepare pharmaceutical compositions. Such combination therapylowers the effective dose of the anti-psychotic drug and thereby reducesthe side effects of the anti-psychotic drugs. Some typicalanti-psychotic drugs that may be used in the practice of the inventioninclude Haldol. Some atypical anti-psychotic drugs include Ziprasidone,Olanzapine, Resperidone, and Quetiapine.

[0881] Compounds of Formula I can be prepared as shown in Scheme 1. Thekey step in the preparation of this class of compounds is the couplingof an azabicyclic moiety with the requisite acid chloride (Lv=Cl), mixedanhydride (e.g., Lv=diphenyl phosphoryl,bis(2-oxo-3-oxazolidinyl)phosphinyl, or acyloxy of the general formulaof O—C(O)—R_(Lv), where R_(Lv) includes phenyl or t-butyl), orcarboxylic acid (Lv=OH) in the presence of an activating reagent.Suitable activating reagents are well known in the art, for examples seeKiso, Y., Yajima, H. “Peptides” pp. 39-91, San Diego, Calif., AcademicPress, (1995), and include, but are not limited to, agents such ascarbodiimides, phosphonium and uronium salts (such as HATU).

Azabicyclo-NH₂+W—C(═O)-Lv→Azabicyclo-N(H)—C(═O)-W  Scheme 1

[0882] Generally, to obtain compounds of Formula I, the carboxylic acidis activated with a uronium salt, preferably HATU (see J. Am. Chem.Soc., 4397 (1993)), in the presence of the azabicyclic moiety and a basesuch as DIEA in DMF to afford the desired amides. Alternatively, thecarboxylic acid is converted to the acyl azide by using DPPA; theappropriate amine precursor is added to a solution of the appropriateanhydride or azide to give the desired final compounds. In some cases,the ester (Lv being OMe or OEt) may be reacted directly with the amineprecursor in refluxing methanol or ethanol to give the compounds ofFormula I.

[0883] Certain 6-substituted-[2.2.2]-3-amines (Azabicyclo I) are knownin the art. The preparation of compounds where R₂ is present isdescribed in Acta Pol. Pharm. 179-85 (1981). Alternatively, the6-substituted-[2.2.2]-3-amine can be prepared by reduction of an oximeor an imine of the corresponding 6-substituted-3-quinuclidinone bymethods known to one of ordinary skill in the art (see J. LabelledCompds. Radiopharm., 53-60 (1995), J. Med. Chem. 988-995, (1998), Synth.Commun. 1895-1911 (1992), Synth. Commun. 2009-2015 (1996)).Alternatively, the 6-substituted-[2.2.2]-3-amine can be prepared from a6-substituted-3-hydroxyquinuclidine by Mitsunobu reaction followed bydeprotection as described in Synth. Commun. 1895-1911 (1995).Alternatively, the 6-substituted-[2.2.2]-3-amine can be prepared byconversion of a 6-substituted-3-hydroxyquinuclidine into thecorresponding mesylate or tosylate, followed by displacement with sodiumazide and reduction as described in J. Med. Chem. 587-593 (1975).

[0884] The oximes can be prepared by treatment of the 3-quinuclidinoneswith hydroxylamine hydrochloride in the presence of base. The imines canbe prepared by treatment of the 3-quinuclidinones with a primary amineunder dehydrating conditions. The 3-hydroxyquinuclidines can be preparedby reduction of the 3-quinuclidinones. The6-substituted-3-quinuclidinones can be prepared by known procedures (seeJ. Gen. Chem. Russia 3791-3795, (1963), J. Chem. Soc. Perkin Trans.I409-420 (1991), J. Org. Chem. 3982-3996 (2000)).

[0885] One of ordinary skill in the art will recognize that the methodsdescribed for the reaction of the unsubstituted3-amino-1-azabicyclo[2.2.1]heptane (R₂=absent) are equally applicable tosubstituted compounds (R₂≠H). For where Azabicyclo is II, compoundswhere R₂ is present can be prepared from appropriately substituted nitroalcohols using procedures described in Tetrahedron (1997), 53, p. 11121as shown below. Methods to synthesize nitro alcohols are well known inthe art (see J. Am. Chem. Soc. (1947), 69, p 2608). The scheme below isa modification of the synthesis ofexo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt, described in detail herein, to show how toobtain these amine precursors. The desired salt can be made usingstandard procedures.

[0886] Compounds for Azabicyclo II where R₂ is present can also beprepared by modification of intermediates described in the synthesis ofexo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt, described in detail herein. For example,Int 6 can be oxidized to the aldehyde and treated with an organometallicreagent to provide Int 20 using procedures described in Tetrahedron(1999), 55, p 13899. Int 20 can be converted into the amine usingmethods described for the synthesis ofexo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt. Once the amine is obtained, the desiredsalt can be made using standard procedures.

[0887] The schemes used are for makingexo-³-amino-1-azabicyclo[2.2.1]heptane. However, the modificationsdiscussed are applicable to make the endo isomer also.

[0888] There are several methods by which the amine precursor forAzabicyclo III and Azabicyclo IV can be obtained:

[0889] where Lv can be —CH₂Ph, —CH(Me)Ph, —OH, —OMe, or —OCH₂Ph.

[0890] The respective amine precursors for Azabicyclo III and AzabicycloIV can be prepared by reduction of an oxime or an imine of thecorresponding N-2-azabicyclo[2.2.1]-heptanone by methods known to oneskilled in the art (see J. Labelled Compds. Radiopharm., 53-60 (1995),J. Med. Chem. 988-995, (1998), Synth. Commun. 1895-1911 (1992), Synth.Commun. 2009-2015 (1996)). The oximes can be prepared by treatment ofthe N-2-azabicyclo[2.2.1]heptanones with hydroxylamine hydrochloride inthe presence of a base. The imines can be prepared by treatment of theN-2-azabicyclo[2.2.1]-heptanones with a primary amine under dehydratingconditions. The N-2-azabicyclo[2.2.1]heptanones can be prepared by knownprocedures (see Tet. Lett. 1419-1422 (1999), J. Med. Chem. 2184-2191(1992), J. Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995)).

[0891] The exo- and endo-1-azabicyclo[3.2.1]octan-3-amines are preparedfrom 1-azabicyclic[3.2.1]octan-3-one (Thill, B. P., Aaron, H. S., J.Org. Chem., 4376-4380 (1968)) according to the general procedure asdiscussed in Lewin, A. H., et al., J. Med. Chem., 988-995 (1998).

[0892] One of ordinary skill in the art will also recognize that themethods described for the reaction of the unsubstituted1-azabicyclo[3.2.1]octan-3-amine or 1-azabicyclo[3.2.2]nonan-3-amine(R₂=absent) are equally applicable to substituted compounds (R₂present). The R₂ substituent may be introduced as known to one skilledin the art through standard alkylation chemistry. Exposure of1-azabicyclo[3.2.1]octan-3-one or 1-azabicyclo[3.2.2]nonan-3-one to ahindered base such as LDA (lithium diusopropylamide) in a solvent suchas THF or ether between 0° C. to −78° C. followed by the addition of analkylating agent (R₂Lv, where Lv=Cl, Br, I, OTs, etc.) will, after beingallowed to warm to about 0° C. to rt followed by an aqueous workup,provide the desired compound as a mixture of isomers. Chromatographicresolution (flash, HPLC, or chiral HPLC) will provided the desiredpurified alkylated ketones. From there, formation of the oxime andsubsequent reduction will provide the desired endo or exo isomers.

[0893] It will be apparent to those skilled in the art that therequisite carboxylic acids are either commercially available or can beobtained through synthesis via literature procedures or through theslight modification thereof.

[0894] When W is furan, oxazole, pyrrole, 5-thiazole, or thiophene, thecarboxylic acid is activated with a uronium salt, preferably HATU, inthe presence of the azabicyclic moiety and a base such as DIEA in DMF toafford the desired amides. In the case where W is a 2-thiazole, or2-oxazole, the amide bond is formed by the reaction of the amine andester (Lv=OEt) in an alcoholic solvent (see Liebigs Ann. Chem.,1216-1231 (1980)).

[0895] The thiophene carboxylic acids required in Examples 3, 16-18 canbe synthesized from the corresponding aldehydes by oxidation with NaClO₂as described in J. Org. Chem., (1980), 45, 1176. The requisite aldehydescan be made as described in J. Med. Chem., 1585-1599 (1997). An arylboronic acid is reacted with a bromothiophene in the presence of apalladium (0) source, such as tetrakis-(triphenylphosphine)palladium(0), and a base, preferably aqueous sodium carbonate. The reaction worksbest if heated at reflux in THF/water for 24 hr. The thiophenecarboxylic acids of Examples 6-10 are prepared by similar methods as inExample 3 with modifications as described herein. The furan andthiophene carboxylic acids required for Examples 1, 2, and 11 areavailable commercially.

[0896] The thiophene carboxylic acids for Examples 12-13 are synthesizedfrom the corresponding esters by base catalyzed hydrolysis. Typicalhydrolysis procedures are well known in the art. Preferably, thethiophene ester is treated with aqueous lithium hydroxide in a solventsuch as dioxane. The esters are commercially available. The thiophenecarboxylic acid for Example 14 is synthesized by a two-step sequencebeginning with reaction of a bromothiophene-carbaldehyde with theappropriate thiophenol or phenol as described in Coll. Czech. Chem.Commun., 2360-2363 (1980). Namely, the sodium salt of the thiophenol orphenol is formed by treatment with a strong base like sodium hydride.The sodium salt is then reacted with a bromothiophene in a solvent suchas acetone. The thiophene-carbaldehydes are oxidized to thecorresponding carboxylic acids by treating with sodium chlorite asdescribed in J. Org. Chem. (1980) 45, 1176. The carboxylic acid forExample 15 is made using the same general procedure, making non-criticalchanges.

[0897] When W is thiazole, the required acid for Example 19 is preparedby nucleophilic addition of the requisite phenol or thiophenol to theethyl 2-bromo-1,3-thiazole-5-carboxylate according to the proceduredescribed in Helv. Chim. Acta., 2002-2022 (1997). Preferably, in EtOHutilizing K₂CO₃ as a base (Scheme 3). The esters are hydrolyzed to thecorresponding carboxylic acids by procedures well known in the art. The2-bromo-1,3-thiazole is prepared by the method described in RocznikiChemii Ann. Soc. Chim. Polonorum, 1647-1658 (1972). The aryl1,3-thiazole for Example 20 is prepared according to the procedure ofHuntress and Pfister in J. Am. Chem. Soc., 2167-2169 (1943). The1,3-thiazole-5-carboxylic acid required in Example 21 can be synthesizedfrom the corresponding esters by base hydrolysis via procedures wellknown in the art. The requisite esters can be prepared by a Suzukireaction as described in J. Med. Chem., 4985-92 (1995). An aryl boronicacid is reacted with a bromothiazole ester in the presence of apalladium (0) source, such as tetrakis-(triphenylphosphine)palladium(0), and a base, preferably aqueous sodium carbonate.

[0898] The 5-substituted-1,3-oxazole-2-ester for Example 23 issynthesized according to procedures described in J. Pharm. Soc. Japan,305-7 (1956) as shown in Scheme 4. The5-substituted-1,3-thiazole-2-ester for Example 24 is synthesizedaccording to procedures described in Chem. Pharm. Bull., 4195-4198(1982).

[0899] The furans for Examples 25-28 are commercially available or canbe prepared from their corresponding aldehydes by oxidation or esters byreduction as described for Example 3. In the event that the furan is notcommercially available, it can be prepared by the method of Bussolariand Rehbom described in Org. Lett. 965-7 (1999). Furan Examples 29-30are prepared in a convergent means by a direct palladium catalyzedSuzuki coupling of, for example,N-[1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-furan-2-carboxamide, with therequisite boronic acid by the method described in Org. Lett. 965-7(1999), to yield directly the desired aryl amides (Scheme 5).

[0900] One of ordinary skill in the art would recognize that Examples 4,and 31 are prepared by reduction of the corresponding aryl nitrocompounds by methods well known in the art, preferably by reduction withPd/C in an alcoholic solvent such as EtOH under H₂. The carboxylic acidfor Example 32 is prepared by a Pd(0) catalyzed Sonogashira coupling of5-bromo-2-furaldehyde and phenyl acetylene as described in TetrahedronLett., 4467-70 (1975). The resulting aldehyde is converted to thedesired analog by methods as described for Example 25. Example 33 isprepared by addition of the sodium salt of phenol toN-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-furan-2-carboxamide.The requisite acid for Example 34 is prepared by bromination ofmethyl-5-bromo-1-methyl-1H-pyrrole-2-carboxylate, followed by similarPd-catalyzed coupling as described for Example 3.

[0901] The 1,3-oxazole-2-carboxylic acid required for Example 35 isprepared by the method described in J. Pharm. Sci. Japan 305-7, (1956).The 2-phenyl-1,3-oxazole-5-carboxylic acid required for Example 36 isprepared by the method described in Chem. Heterocycl. Compd.(Engl.Transl.), 654-663, (1986). 2-Phenyl-1,3-oxazole-4-carboxylic acidrequired for Example 37 is prepared as described by Korte and Stoeriko,in Chem. Ber., 1033-1042, (1960). The 5-phenylisoxazole-3-carboxylicacid for Example 38 is prepared by the method of Vaughan and Spencer asdescribed in J. Org. Chem. 1160-4, (1960).

[0902] Thioamides, such as Example 39, can be prepared from therequisite thioester by direct displacement of the thioester with anaminoazabicyclic compound. The thioester can be prepared as described inJ. Organometallic Chem., 95-98 (1987). One of ordinary skill in the artwould quickly identify that compounds such as Example 39 could also beprepared directly from the amides exemplified throughout this patent bydirect treatment with a reagent such and Lawesson's reagent (seeLawesson et. al. in Bull. Soc. Chim. Belg., 229 (1978)) or P₄S₁₀ (seeChem. Rev., 45 (1961)). Alternatively one can react a dithiocarboxylicester with the corresponding amino-azabicyclo compound to form the samethioamide.

[0903] Preparation of the 2.2.1 Amines:

Synthesis of exo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt

[0904]

[0905] Step A. Preparation of 2-(benzoyloxy)-1-nitroethane (Int 1).

[0906] Benzoyl chloride (14.9 mL, 128 mmol) is added to a stirredsolution of nitroethanol (9.2 mL, 128 mmol) in dry benzene (120 mL). Thesolution is refluxed for 24 hr and then concentrated in vacuo. The crudeproduct is purified by flash chromatography on silica gel. Elution withhexanes-EtOAc (80:20) affords Int 1 as a white solid (68% yield): ¹H NMR(CDCl₃) δ8.0, 7.6, 7.4, 4.9, 4.8.

[0907] Step B. Preparation of ethyl E-4-(benzylamino)-2-butenoate (Int2).

[0908] Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, tech grade) is addedto a stirred solution of benzylamine (16 mL, 146 mmol) in CH₂Cl₂ (200mL) at rt. The reaction mixture stirs for 15 min, and is diluted withether (1 L). The mixture is washed with saturated aqueous NaHCO₃solution (3x) and water, dried over Na₂SO₄, filtered and concentrated invacuo. The residue is purified by flash chromatography on silica gel.Elution with hexanes-EtOAc (70:30) affords Int 2 as a clear oil (62%yield): ¹H NMR (CDCl₃) δ7.4-7.2, 7.0, 6.0, 4.2, 3.8, 3.4, 2.1-1.8, 1.3.

[0909] Step C. Preparation oftrans-4-nitro-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int3).

[0910] A solution of Int 1 (6.81 g, 34.9 mmol) and Int 2 (7.65 g, 34.9mmol) in EtOH (70 mL) stirs at rt for 15 h and is then concentrated invacuo. The residue is diluted with ether (100 mL) and saturated aqueousNaHCO₃ solution (100 mL). The organic layer is separated and dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withhexanes-EtOAc (85:15) affords Int 3 as a clear oil (76% yield): ¹H NMR(CDCl₃) δ7.4-7.3, 4.8-4.7, 4.1, 3.8-3.6, 3.3-3.0, 2.7-2.6, 2.4-2.3, 1.2.

[0911] Step D. Preparation oftrans-4-amino-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int4).

[0912] A mixture of Int 3 (3.28 g, 11.2 mmol) and RaNi (1.5 g) in EtOH(100 mL) is placed in a Parr bottle and hydrogenated for 4 h under anatmosphere of hydrogen (46 psi) at rt. The mixture is filtered through apad of Celite, and the solvent is removed in vacuo to afford Int 4 as aclear oil (100% yield): ¹H NMR (300 MHz, CDCl₃) δ7.3-7.2, 4.1, 3.6, 3.2,3.0-2.9, 2.8, 2.8-2.6, 2.6-2.4, 2.30-2.2, 1.2.

[0913] Step E. Preparation oftrans-4-(1,1-dimethylethoxycarbonylamido)-1-(phenylmethyl)-3-pyrrolidineaceticacid ethyl ester (Int 5).

[0914] Di-tert-butyldicarbonate (3.67 g, 16.8 mmol) is added to astirred solution of Int 4 (2.94 g, 11.2 mmol) in CH₂Cl₂ (30 mL) cooledin an ice bath. The reaction is allowed to warm to rt and stirredovernight. The mixture is concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withhexanes-EtOAc (80:20) affords Int 5 as a white solid (77% yield): ¹H NMR(300 MHz, CDCl₃) δ7.4-7.2, 5.1-4.9, 4.1, 4.0-3.8, 3.6, 3.2-3.0, 2.8-2.6,2.5-2.4, 2.3-2.1, 1.4, 1.3.

[0915] Step F. Preparation of trans(tert-butoxycarbonylamino)-4-(2-hydroxyethyl)-1-(N-phenylmethyl)pyrrolidine (Int 6).

[0916] LiAlH₄ powder (627 mg, 16.5 mmol) is added in small portions to astirred solution of Int 5 (3.0 g, 8.3 mmol) in anhydrous THF (125 mL) ina −5° C. bath. The mixture is stirred for 20 min in a −5° C. bath, thenquenched by the sequential addition of water (0.6 mL), 15% (w/v) aqueousNaOH (0.6 mL) and water (1.8 mL). Excess anhydrous K₂CO₃ is added, andthe mixture is stirred for 1 h, then filtered. The filtrate isconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel. Elution with EtOAc affords Int 6 as a white solid (94%yield): ¹H NMR (CDCl₃) δ7.4-7.3, 5.3-5.2, 4.1-4.0, 3.9-3.7, 3.3-3.2,2.8-2.7, 2.3-2.1, 1.7, 1.5.

[0917] Int 6 is a racemic mixture that can be resolved viachromatography using a Diacel chiral pack AD column. From the twoenantiomers thus obtained, the (+)-enantiomer, [α]²⁵ _(D)+35 (c 1.0,MeOH), gives rise to the corresponding enantiomerically pure exo-4-Sfinal compounds, whereas the (−)-enantiomer, [α]²⁵ _(D)−34 (c 0.98,MeOH), gives rise to optically pure exo-4-R final compounds. The methodsdescribed herein use the (+)-enantiomer of Int 6 to obtain the opticallypure exo-4-S final compounds. However, the methods used are equallyapplicable to the (−)-enantiomer of Int 6, making non-critical changesto the methods provided herein to obtain the optically pure exo-4-Rfinal compounds.

[0918] Step G. Preparation of exo3-(tert-butoxycarbonylamino)-1-azabicyclo[2.2.1]heptane (Int 7).

[0919] TEA (8.0 g, 78.9 mmol) is added to a stirred solution of Int 6(2.5 g, 7.8 mmol) in CH₂Cl₂ (50 mL), and the reaction is cooled in anice-water bath. CH₃SO₂Cl (5.5 g, 47.8 mmol) is then added dropwise, andthe mixture is stirred for 10 min in an ice-water bath. The resultingyellow mixture is diluted with saturated aqueous NaHCO₃ solution,extracted with CH₂Cl₂ several times until no product remains in theaqueous layer by TLC. The organic layers are combined, washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue isdissolved in EtOH (85 mL) and is heated to reflux for 16 h. The reactionmixture is allowed to cool to rt, transferred to a Parr bottle andtreated with 10% Pd/C catalyst (1.25 g). The bottle is placed under anatmosphere of hydrogen (53 psi) for 16 h. The mixture is filteredthrough Celite, and fresh catalyst (10% Pd/C, 1.25 g) is added.Hydrogenolysis continues overnight. The process is repeated three moretimes until the hydrogenolysis is complete. The final mixture isfiltered through Celite and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel. Elution withCHCl₃—MeOH—NH₄OH (90:9.5:0.5) affords Int 7 as a white solid (46%yield): ¹H NMR (CDCl₃) δ5.6-5.5, 3.8-3.7, 3.3-3.2, 2.8-2.7, 2.0-1.8,1.7-1.5, 1.5.

[0920] Step H. Preparation of exo-3-amino-1-azabicyclo[2.2.1]heptanebis(hydro-para-toluenesulfonate).

[0921] Para-toluenesulfonic acid monohydrate (1.46 g, 7.68 mmol) isadded to a stirred solution of Int 7 (770 mg, 3.63 mmol) in EtOH (50mL). The reaction mixture is heated to reflux for 10 h, followed bycooling to rt. The precipitate is collected by vacuum filtration andwashed with cold EtOH to give exo-[2.2.1]-Amine as a white solid (84%yield): ¹NMR (CD₃OD) δ7.7, 7.3, 3.9-3.7, 3.7-3.3, 3.2, 2.4, 2.3-2.2,1.9-1.8. The corresponding amines can be obtained by using the resolvedInt 6 to give exo-(4R)-[2.2.1]-3-Amine and exo-(4S)-[2.2.1]-3-Amine.

Synthesis of endo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt

[0922]

[0923] Step I. Preparation of ethyl5-hydroxy-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate (Int 10).

[0924] Absolute EtOH (92.0 mL, 1.58 mol) is added to a mechanicallystirred suspension of potassium ethoxide (33.2 g, 395 mmol) in drytoluene (0.470 L). When the mixture is homogeneous, 2-pyrrolidinone(33.6 g, 395 mmol) is added, and then a solution of diethyl oxalate(53.1 mL, 390 mmol) in toluene (98 mL) is added via an addition funnel.After complete addition, toluene (118 mL) and EtOH (78 mL) is addedsequentially. The mixture is heated to reflux for 18 h. The mixture iscooled to rt and aqueous HCl (150 mL of a 6.0 M solution) is added. Themixture is mechanically stirred for 15 min. The aqueous layer isextracted with CH₂Cl₂, and the combined organic layers are dried overMgSO₄, filtered and concentrated in vacuo to a yellow residue. Theresidue is recrystallized from EtOAc to afford Int 10 as a yellow solid(38% yield): ¹H NMR (CDCl₃) δ11.4, 7.4, 4.3, 3.4, 2.6, 1.3.

[0925] Step J. Preparation of ethylcis-3-hydroxy-2-oxopiperidine-4-carboxylate (Int 11).

[0926] A mixture of Int 10 (15 g, 81 mmol) and 5% rhodium on carbon (2.0g) in glacial acetic acid is placed under an atmosphere of hydrogen (52psi). The mixture is shaken for 72 h. The mixture is filtered throughCelite, and the filtrate is concentrated in vacuo to afford Int 11as awhite solid (98% yield): ¹H NMR (CDCl₃) δ6.3, 4.2, 4.0-3.8, 3.4,3.3-3.2, 2.2, 1.3.

[0927] Step K. Preparation of cis-4-(hydroxymethyl)piperidin-3-ol (Int12).

[0928] Int 11 (3.7 g, 19.9 mmol) as a solid is added in small portionsto a stirred solution of LiAlH₄ in THF (80 mL of a 1.0 M solution) in anice-water bath. The mixture is warmed to rt, and then the reaction isheated to reflux for 48 h. The mixture is cooled in an ice-water bathbefore water (3.0 mL, 170 mmol) is added dropwise, followed by thesequential addition of NaOH (3.0 mL of a 15% (w/v) solution) and water(9.0 mL, 500 mmol). Excess K₂CO₃ is added, and the mixture is stirredvigorously for 15 min. The mixture is filtered, and the filtrate isconcentrated in vacuo to afford Int 12 as a yellow powder (70% yield):¹H NMR (DMSO-d₆) δ4.3, 4.1, 3.7, 3.5-3.2, 2.9-2.7, 2.5-2.3, 1.5, 1.3.

[0929] Step L. Preparation of benzylcis-3-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (Int 13).

[0930] N-(benzyloxy carbonyloxy)succinimide (3.04 g, 12.2 mmol) is addedto a stirred solution of Int 12 (1.6 g, 12.2 mmol) in saturated aqueousNaHCO₃ (15 mL) at rt. The mixture is stirred at rt for 18 h. The organicand aqueous layers are separated. The aqueous layer is extracted withether (3X). The combined organic layers are dried over anhydrous K₂CO₃,filtered and concentrated in vacuo to afford Int 13 as a yellow oil (99%yield): ¹H NMR (CDCl₃) δ7.4-7.3, 5.2, 4.3, 4.1, 3.8-3.7, 3.0-2.8, 2.1,1.9-1.7, 1.4.

[0931] Step M. Preparation of benzylcis-3-hydroxy-4-[(4-methylphenyl)sulfonyloxymethyl]piperidine-1-carboxylate (Int 14).

[0932] Para-toluenesulfonyl chloride (1.0 g, 5.3 mmol) is added to astirred solution of Int 13 (3.6 g, 5.3 mmol) in pyridine (10 mL) in a−15° C. bath. The mixture is stirred for 4 h, followed by addition ofHCl (4.5 mL of a 6.0 M solution). CH₂Cl₂ (5 mL) is added. The organicand aqueous layers are separated. The aqueous layer is extracted withCH₂Cl₂. The combined organic layers are washed with brine, dried overMgSO₄, filtered and concentrated in vacuo to afford Int 14 as acolorless oil (78% yield): ¹H NMR (CDCl₃) δ7.8, 7.4-7.2, 5.1, 4.3-4.2,4.1, 3.9-3.8, 2.9-2.7, 2.4, 1.9, 1.6-1.3.

[0933] Step N. Preparation of exo-1-azabicyclo[2.2.1]heptan-3-ol (Int15).

[0934] A mixture of Int 14 (3.6 g, 8.6 mmol) and 10% Pd/C catalyst (500mg) in EtOH (50 mL) is placed under an atmosphere of hydrogen. Themixture is shaken for 16 h. The mixture is filtered through Celite.Solid NaHCO₃ (1.1 g, 13 mmol) is added to the filtrate, and the mixtureis heated in an oil bath at 50° C. for 5 h. The solvent is removed invacuo. The residue is dissolved in saturated aqueous K₂CO₃ solution.Continuous extraction of the aqueous layer using a liquid-liquidextraction apparatus (18 h), followed by drying the organic layer overanhydrous K₂CO₃ and removal of the solvent in vacuo affords Int 15 as awhite solid (91% yield): ¹H NMR δ3.8, 3.0-2.8, 2.6-2.5, 2.4-2.3, 1.7,1.1.

[0935] Step O. Preparation of endo-3-azido-1-azabicyclo[2.2.1]heptane(Int 16).

[0936] To a mixture of Int 15 (1.0 g, 8.9 mmol) and triphenyl phosphine(3.0 g, 11.5 mmol) in toluene-THF (50 mL, 3:2) in an ice-water bath areadded sequentially a solution of hydrazoic acid in toluene (15 mL of ca.2 M solution) and a solution of diethyl azadicarboxylate (1.8 mL, 11.5mmol) in toluene (20 mL). The mixture is allowed to warm to rt and stirfor 18 h. The mixture is extracted with aqueous 1.0 M HCl solution. Theaqueous layer is extracted with EtOAc, and the combined organic layersare discarded. The pH of the aqueous layer is adjusted to 9 with 50%aqueous NaOH solution. The aqueous layer is extracted with CH₂Cl₂ (3X),and the combined organic layers are washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withCHCl₃—MeOH—NH₄OH (92:7:1) affords Int 16 as a colorless oil (41% yield):¹H NMR (CDCl₃) δ4.1, 3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5.

[0937] Step P. Preparation of endo-3-amino-1-azabicyclo[2.2.1]heptanebis(hydro-para-toluenesulfonate).

[0938] A mixture of Int 16 (250 mg, 1.8 mmol) and 10% Pd/C catalyst (12mg) in EtOH (10 mL) is placed under an atmosphere of hydrogen (15 psi).The mixture is stirred for 1 h at rt. The mixture is filtered throughCelite, and the filtrate is concentrated in vacuo. The residue isdissolved in EtOH (10 mL) and para-toluenesulfonic acid monohydrate (690mg, 3.7 mmol) is added. The mixture is stirred for 30 min, and theprecipitate is filtered. The precipitate is washed sequentially withcold EtOH and ether. The precipitate is dried in vacuo to affordendo-[2.2.1]-Amine as a white solid (85% yield): ¹H NMR (CD₃OD) δ7.7,7.3, 4.2, 3.9, 3.6-3.4, 3.3-3.2, 2.4, 2.3, 2.1.

[0939] Preparation of the 3.2.1-Amine:

[0940] exo-1-Azabicyclo[3.2.1]octan-3-amine dihydrochloride(exo-[3.2.1]-Amine):

[0941] A mixture of 1-azabicyclo[3.2.1]octan-3-one hydrochloride (2.80g, 17.3 mmol), ethanol (25 mL), and hydroxylamine hydrochloride (1.56 g,22.4 mmol) is treated with sodium acetate trihydrate (7.07 g, 51.2mmol). The mixture is stirred for 3 h and evaporated in vacuo. Theresidue is diluted with CH₂Cl₂, treated with charcoal, filtered andevaporated. The resulting material is taken up in 1-propanol (45 mL) andheated in a 100° C. oil bath. The solution is treated with sodium metal(6.4 g in portions). Heating is continued for 3 h and the mixture cooledto rt. Water is added carefully and the organic layer is extracted,dried (MgSO₄), filtered, acidified with MeOH/HCl(g), and evaporated.2-Propanol is added and the resulting solid is filtered and dried invacuo to give exo-[3.2.1]-Amine in 49% yield. MS for C₇H₁₄N₂.(HCl)₂(ESI) (M+H)⁺ m/z=127.

[0942] Endo-1-azabicyclo [3.2.1]octan-3-amine dihydrochloride(Endo-[3.2.1]-Amine):

[0943] A mixture of 1-azabicyclo[3.2.1]octan-3-one hydrochloride (2.80g, 17.3 mmol), ethanol (25 mL), and hydroxylamine hydrochloride (1.56 g,22.4 mmol) is treated with sodium acetate trihydrate (7.07 g, 51.2mmol). The mixture is stirred for 3 h and evaporated in vacuo. Theresidue is diluted with CH₂Cl₂, treated with charcoal, filtered andevaporated. The resulting oxime (3.1 mmol) is treated with acetic acid(30 mL) and hydrogenated at 50 psi over PtO₂ (50 mg) for 12 h. Themixture is then filtered and evaporated. The residue is taken up in aminimal amount of water (6 mL) and the pH is adjusted to >12 using solidNaOH. The mixture is then extracted with ethyl acetate (4×25 mL), driedover MgSO₄, filtered, treated with ethereal HCl, and evaporated to giveendo-[3.2.1]-Amine.

[0944] 1-Azabicyclo[3.2.1]octan-3-amine:

[0945] Preparation of the 3R,5R-[3.2.1]-Amine:

[0946] This amine can also be prepared according to the followingmethod:

[0947] (3S)-1-[(S)-1-Phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid:

[0948] According to the literature procedure (Nielsen et al. J. Med.Chem 1990, 70-77), a mixture of itaconic acid (123.17 g, 946.7 mmol) and(S)-(−)-α-methyl benzylamine (122.0 mL, 946.4 mmol) are heated (neat) ina 160° C. oil bath for 4 h. Upon cooling, MeOH (˜200 mL) is added andthe resulting solid collected by filtration. The solid is treated withEtOH (˜700 mL) and warmed using a steam bath until ˜450 mL solventremained. After cooling to rt, the solid is collected and dried toafford 83.2 g as a crystalline solid: [α]²⁵ _(D)=−80 (c 0.97, DMSO). ¹HNMR (400 MHz, DMSO-d₆) δ12.66, 7.20-7.40, 5.23, 3.40-3.55, 3.10-3.25,2.40-2.65, 1.45; MS (EI) m/z 233 (M⁺).

[0949] (3S)-1-[(S)-1-Phenethyl]-3-(hydroxymethyl)pyrrolidine:

[0950] A suspension(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid (82.30 g,352.8 mmol) in Et₂O (200 mL) is added in small portions to a slurry ofLiAlH₄ (17.41 g, 458.6 mmol) in Et₂O (700 mL). The mixture begins toreflux during the addition. The addition funnel containing thesuspension is rinsed with Et₂O (2×50 mL), and the mixture is heated in a50° C. oil bath for an additional 2 h and first allowed to cool to rtand then further cooled using an ice bath. The mixture is carefullytreated with H₂O (62 mL). The resulting precipitate is filtered, rinsedwith Et₂O, and discarded. The filtrate is concentrated to a yellow oil.When EtOAc is added to the oil, a solid began to form. Hexane is thenadded, and the mixture is filtered and the solid is dried to afford 43.3g. [α]²⁵ _(D)=−71 (c 0.94, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.20-7.45,3.60-3.70, 3.40-3.60, 3.19, 3.05-3.15, 2.35-2.55, 2.25-2.35, 1.95-2.10,1.75-1.90, 1.42; HRMS (FAB) calcd for C₁₃H₁₉NO (MH⁺) 206.1545, found206.1532.

[0951] (3R)-1-[(S)-l-Phenethyl]-3-(cyanomethyl)pyrrolidine:

[0952] A solution of(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine (42.75 g, 208.23mmol) in chloroform (350 mL) is heated to reflux under N₂. The solutionis treated with a solution of thionyl chloride (41.8 mL, 573 mmol) inchloroform (40 mL) dropwise over 45 min. The mixture is stirred for anadditional 30 min, is cooled and concentrated. The residue is dilutedwith H₂O (˜200 mL), 1 N NaOH is added until a pH˜8 (pH paper). A smallportion (˜50 mL) of sat. NaHCO₃ is added and the basic mixture isextracted with EtOAc (3×400 mL), washed with brine, dried over MgSO₄,filtered and concentrated to give 46.51 g of(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine: MS (ESI+) m/z224.2 (MH⁺). The chloride (46.35 g, 208.0 mmol) is transferred to aflask, DMSO (200 mL) is added, and the solution is treated with NaCN(17.84 g, 363.9 mmol). The mixture is heated under N₂ in a 100° C. oilbath overnight and is cooled. The brown mixture is poured into H₂O (300mL) and is extracted with EtOAc (1000 mL in portions). The combinedorganic layer is washed with H₂O (6×˜50 mL), brine (˜100 mL), dried(MgSO₄), filtered and concentrated to give 40.61 g of an oil: ¹H NMR(400 MHz, CDCl₃) δ7.20-7.40, 3.26, 2.70-2.85, 2.40-2.60, 2.27,2.10-2.20, 1.50-1.70, 1.41; MS (ESI+) for m/z 215.2 (M+H⁺).

[0953] (3R)-Methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate:

[0954] Acetyl chloride (270 mL, 3.8 mol) is carefully added to a flaskcontaining chilled (0° C.) methanol (1100 mL). After the addition iscomplete, the acidic solution is stirred for 45 min (0° C.) and then(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine (40.50 g, 189.0mmol) in methanol (200 mL) is added. The ice bath is removed and themixture is stirred for 100 h at rt. The resulting suspension isconcentrated. Water (˜600 mL) is added, the mixture stirred for 45 minand then the pH is adjusted (made basic) through the addition of ˜700 mLsat. aq. NaHCO₃. The mixture is extracted with EtOAc (3×300 mL). Thecombined organic layers are washed with brine, dried (MgSO₄), filteredthrough celite and concentrated to give 36.86 g as an oil: ¹H NMR (400MHz, CDCl₃) δ7.20-7.40, 3.69, 3.30-3.40, 2.85-2.95, 2.40-2.70,2.00-2.20, 1.10-1.65; MS (ESI+) m/z 248.2 (M+H⁺).

[0955] (5R)-1-Azabicyclo[3.2.1]octan-3-one hydrochloride:

[0956] A solution of (3R)-methyl1-[(S)-1-phenylethyl]pyrrolidine-3-acetate (25.72 g, 104.0 mmol) in THF(265 mL) is cooled under N₂ in a CO₂/acetone bath. Next, ICH₂Cl (22.7mL, 312.0 mmol) is added, and the mixture stirred for 30 min. A solutionof 2.0 M lithium diisopropylamide (heptane/THF/ethylbenzene, 156 mL, 312mmol) is added slowly over 30 min. The internal temperature reached amaximum of −40° C. during this addition. After 1 h, sat. NH₄Cl (100 mL)is added and the mixture is allowed to warm to rt. The organic layer isseparated, dried (MgSO₄), filtered and concentrated. The resulting foamis chromatographed (300 g SiO₂, CHCl₃—MeOH—NH₄OH (89:10:1) followed byCHCl₃—MeOH (3:1). The product fractions are pooled and concentrated toafford (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octanechloride (10.12 g) as a foam (MS (ESI+) m/z 230.1 (M+H⁺). This foam(10.1 g, 38 mmol) is taken up in MeOH (500 mL), 10% Pd(C) (3.0 g) addedand the mixture is hydrogenated (45 psi) overnight. The mixture isfiltered and re-subjected to the reduction conditions (9.1 g, 10% Pd/C,50 psi). After 5 h, TLC indicates the consumption of the(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride.The mixture is filtered, concentrated and triturated (minimal iPrOH) togive 3.73 g in two crops, as a solid: [α]²⁵ _(D)=33 (c 0.97, DMSO); HRMS(FAB) calcd for C₇H₁₁NO (M+H⁺) 126.0919, found 126.0937.

[0957] (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride:

[0958] To a flask containing (5R)-1-azabicyclo[3.2.1]octan-3-onehydrochloride (3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g,29.4 mmol), and ethanol (130 mL) is added sodium acetate trihydrate(9.23 g, 67.8 mmol). The mixture stirred for 3 h and is filtered andconcentrated. The resulting white solid is taken up in n-propanol (100mL) and sodium (˜13.6 g, 618 mmol) is added in 20-25 portions. Thereaction spontaneously begins to reflux, and the reaction is heated inan oil bath (100° C.). The addition is complete in ˜20 min and themixture solidifies after ˜40 min. The oil bath is removed and n-propanol(2×25 mL) is added dissolving the remaining sodium metal. The mixture iscarefully quenched through the dropwise addition of H₂O (100 mL).Saturated aq. NaCl (20 mL) is added, and the layers are separated. Theorganic layer is dried (MgSO₄), filtered, treated with freshly preparedMeOH/HCl, and concentrated. The resulting solid is triturated with 30 mLEtOH, filtered and dried in vaccuo to afford 3.51 g as a white solid:[α]²⁵ _(D)=−3 (c 0.94, DMSO); ¹H NMR (400 MHz, DMSO-d₆)δ3.60-3.80,2.95-3.10, 2.65-2.75, 1.90-2.15, 1.70-1.90; HRMS (FAB) calcd for C₇H₁₄N₂(M+H⁺) 127.1235, found 127.1235.

[0959] Preparation of the 3.2.2 Amines:

[0960] Preparation of tert-butyl4-(2-oxopropylidene)piperidine-1-carboxylate (Int 101):

[0961] Sodium hydride (60% oil dispersion, 2.01 g, 50.2 mmol) was washedwith pentane (3X) and suspended in dry THF (40 mL). The solution wascooled to 0°0 C. before diethyl (2-oxopropyl)phosphonate (9.75 g, 50.2mmol) was added dropwise. After complete addition, the solution waswarmed to rt and stirred for 30 min. tert-Butyl4-oxo-1-piperidinecarboxylate (5.0 g, 25.1 mmol) was added in portionsover 10 min, followed by stirring at rt for 2 h. A saturated aqueoussolution of ammonium chloride was added, followed by dilution withether. The organic layer was extracted with water. The organic layer isdried over anhydrous MgSO₄, filtered and concentrated to a yellow oil.The crude product was purified by flash chromatography on silica gel.Elution with hexanes-ether (60:40) gave 4.5 g (75%)of Int 101 as a whitesolid: ¹NMR (CDCl₃) δ6.2, 3.5, 3.4, 2.9, 2.3, 2.2, 1.5.

[0962] Preparation of tert-butyl 4-(2-oxopropyl)piperidine-1-carboxylate(Int 102):

[0963] A mixture of Int 101 (4.5 g, 19 mmol) and 10% palladium onactivated carbon (450 mg) in EtOH (150 mL) was placed in a Parr bottleand hydrogenated for 5 h at 50 psi. The mixture was filtered throughCelite, and the filtrate was concentrated in vacuo to afford 4.3 g (94%)of Int 102 as a clear oil: ¹H NMR (CDCl₃) δ4.1, 2.8, 2.4, 2.2, 2.0, 1.7,1.5, 1.1.

[0964] Preparation of tert-butyl4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate (Int 103):

[0965] To a stirred solution lithium hexamethyldisilylamide in THF (20.0mL, 1.0 M) in a −78° C. bath was added chlorotrimethylsilane (11.0 mL,86.4 mmol) dropwise. The mixture was stirred at −78° C. for 20 min,followed by addition of 102 (3.21 g, 13.3 mmol) in a solution of THF (50mL) dropwise. After complete addition, the mixture was stirred at −78°C. for 30 min. The mixture was warmed to 0° C. in an ice-water bath andphenyltrimethylammonium tribromide (5.25 g, 14.0 mmol) was added. Themixture was stirred in an ice-bath for 30 min, followed by the additionof water and ether. The aqueous layer was washed with ether, and thecombined organic layers were washed with saturated aqueous sodiumthiosulfate solution. The organic layer was dried over anhydrous MgSO₄,filtered and concentrated in vacuo to afford a yellow oil. The crudeproduct was purified by flash chromatography on silica gel. Elution withhexanes-ether (60:40) gave 2.2 g (52%) of Int 103 as a lt. yellow oil:¹H NMR (CDCl₃) δ4.2-4.1, 3.9, 2.8, 2.7, 2.6, 2.1-2.0, 1.7, 1.5,1.2-1.1.2.

[0966] Preparation of 1-bromo-3-piperidin-4-ylacetone trifluoroacetate(Int 104):

[0967] To a stirred solution of 103 (2.2 g, 6.9 mmol) in CH₂Cl₂ (30 mL)in an ice-water bath was added trifluoroacetic acid (10 mL, 130 mmol).The mixture was stirred at 0° C. for 30 min. The volatiles were removedin vacuo to afford 2.0 g (87%) of Int 104 as a yellow residue: MS (ESI)for C₈H₁₅BrNO [M+H] m/e 220.

[0968] Preparation of 1-azabicyclo[3.2.2]nonan-3-one (Int 105):

[0969] To a stirred solution of DIEA (13 mL) in acetoniltrile (680 mL)at reflux temperature was added a solution of Int 104(2.0 g, 6.0 mmol)in acetonitrile (125 mL) over a 4 h period via syringe pump. The mixturewas kept at reflux temperature overnight. The mixture was concentratedin vacuo and the remaining residue was partitioned between a saturatedaqueous K₂CO₃ solution and CHCl₃—MeOH (90:10). The aqueous layer wasextracted with CHCl₃—MeOH (90:10), and the combined organic layers weredried over MgSO₄, filtered and concentrated in vacuo to a brown oil. Thecrude product was purified by flash chromatography on silica gel.Elution with CHCl₃—MeOH—NH₄OH (95:4.5:0.5) gave 600 mg (72%) of Int 105as a clear solid: ¹H NMR (CDCl₃) δ3.7, 3.3-3.2, 3.1-3.0, 2.7, 2.3,2.0-1.8.

[0970] Preparation of 1-azabicyclo[3.2.2]nonan-3-aminebis(4-methylbenzenesulfonate) ([3.2.2]-Amine):

[0971] To a stirred mixture of Int 105 (330 mg, 2.4 mmol) and sodiumacetate.trihydrate (670 mg, 4.8 mmol) in EtOH (6.0 mL) was addedhydroxylamine.hydrochloride (200 mg, 2.8 mmol). The mixture was stirredat rt for 10 h. The mixture was filtered and the filtrate wasconcentrated in vacuo to a yellow solid. To a solution of the solid (350mg, 2.3 mmol) in n-propanol (30 mL) at reflux temperature was addedsodium metal (2.0 g, 87 mmol) in small portions over 30 min. Heating atreflux was continued for 2 h. The solution is cooled to rt and brine isadded. The mixture is extracted with n-propanol, and the combinedorganic layers are concentrated in vacuo. The residue was taken up inCHCl₃ and the remaining solids were filtered. The filtrate was driedover anhydrous MgSO₄, filtered and concentrated in vacuo to a clearsolid. To a stirred solution of the solid (320 mg, 2.3 mmol) in EtOH (4mL) was added p-toluenesulfonic acid monohydrate (875 mg, 4.6 mmol). Thesolution was warmed in a water bath to 45° C. for 30 min, followed byconcentration of the solvent to afford 710 mg (62%) of [3.2.2]-Amine asa white solid: ¹H NMR (CD₃OD) δ7.7, 7.3, 4.1-3.9, 3.6-3.4, 2.6-2.5, 2.4,2.2-2.1, 2.1-2.0, 1.9.

[0972] Resolution of stereoisomers:

[0973] The amine can be coupled to form the appropriate amides orthioamides as a racemic mixture. The racemic mixture can then beresolved by chromatography using chiral columns or chiral HPLC,techniques widely known in the art, to provide the requisite resolvedenantiomers 3(R) and 3(S) of said amides or thioamides.

[0974] Coupling the Amine with the Requisite Acid:

[0975] The following examples are provided as examples and are notintended to limit the scope of this invention to only those providedexamples and named compounds. Also, the salts made in the examples areonly exemplary and are not intended to limit the invention. Anypharmaceutically acceptable salt can be made by one of ordinary skill inthe art. Further, the naming of specific stereoisomers is forexemplification, and is not intended to limit in anyway the scope of theinvention. Moreover, the examples provided are carried out using oneamine. However, any amine could be used making non-critical changes butstarting with the amine not identified. The invention includes thefollowing examples in pure stereoisomeric form or as racemic mixtures.

EXAMPLE 1

[0976]Endo-N-(1-azabicyclo[2.2.1]hept-3-yl)-5-bromo-thiophene-2-carboxamide.fumarate:

[0977] Step 1a

[0978] To a stirred suspension of 5-bromo-thiophene-2-carboxylic acid(136 mg, 0.66 mmol) in dry CH₂Cl₂ (3.0 mL) is added TEA (92 μL, 0.66mmol), followed by DPPA (118 μL, 0.55 mmol). In a separate flask, to astirred solution of Amine 2 (200 mg, 0.44 mmol) in water (0.5 mL) andDMF (3.0 mL) is added TEA (245 μL, 1.76 mmol). After 10 min, the aminesolution is rapidly added to the carboxylic acid solution, and thecombined mixture is stirred for 24 h at rt. The reaction mixture ispartitioned between saturated aqueous K₂CO₃ solution and CH₂Cl₂. Theaqueous layer is extracted with CH₂Cl₂, and the combined organic layersare washed with brine, dried over MgSO₄, filtered and concentrated invacuo to a clear residue. The crude product is purified by flashchromatography on silica gel. Elution with CHCl₃—MeOH—NH₄OH (90:9:1)gave 59 mg (45%) of a white solid: MS (ESI) m/e 302 [M+H].

[0979] Step 1b

[0980] To a stirred solution of the product from Step 26a (70 mg, 0.23mmol) in acetone (5 mL) is added a hot solution of fumaric acid (27 mg,0.23 mmol) in IPA (2 mL). The mixture is stirred for 30 min in a 50° C.water bath. The solvents are removed in vacuo and the remaining residueis dissolved in acetone (5 mL). The mixture is stirred overnight at rt.The solid precipitate is collected by filtration and washed withacetone. The solid is dried in vacuo overnight to give 60 mg (62%) ofExample 1 as white solid: ¹H NMR (CD₃OD)δ7.6, 7.2, 6.7, 4.5, 3.6,3.4-3.1, 2.9, 2.1-1.9.

EXAMPLE 2

[0981] N-(exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl)-5-bromo-thiophene-2-5carboxamide.fumarate:

[0982] Step 2a.

[0983] To a stirred suspension of 5-bromo-thiophene-2-carboxylic acid(136 mg, 0.66 mmol) in dry CH₂Cl₂ (3.0 mL) is added TEA (92 μL, 0.66mmol), followed by DPPA (118 μL, 0.55 mmol). In a separate flask, to astirred solution of exo-(4S)-[2.2.1]-3-Amine (200 mg, 0.44 mmol) inwater (0.5 mL) and DMF (3.0 mL) is added TEA (245 μL, 1.76 mmol). After10 min, the amine solution is rapidly added to the carboxylic acidsolution, and the combined mixture is stirred for 24 h at rt. Thereaction mixture is partitioned between saturated aqueous K₂CO₃ solutionand CH₂Cl₂. The aqueous layer is extracted with CH₂Cl₂, and the combinedorganic layers are washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to a clear residue. The crude product is purifiedby flash chromatography on silica gel. Elution with CHCl₃—MeOH—NH₄OH(90:9:1) gave 59 mg (45%) of a white solid: MS (ESI) m/e 302 [M+H].

[0984] To a stirred solution of the product of Step 2a (59 mg, 0.20mmol) in acetone (5 mL) is added a hot solution of fumaric acid (23 mg,0.20 mmol) in IPA (2 mL). The mixture is stirred for 30 min in a 50° C.water bath. The solvents are removed in vacuo and the remaining residueis dissolved in acetone (5 mL). The mixture is stirred overnight at rt.The solid precipitate is collected by filtration and washed withacetone. The solid is dried in vacuo overnight to give 50 mg (61%) ofExample 2 as white solid: ¹H NMR (CD₃OD) δ7.6, 7.2, 6.7, 4.2, 3.7,3.5-3.4, 3.2, 3.0, 2.2, 1.8.

EXAMPLE 3

[0985]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-phenylthiophene-2-carboxamide.fumarate:

[0986] Step 3a

[0987] 5-Bromothiophene-2-carboxaldehyde (1.0 g, 5.2 mmol) is added to asolution of tetrakis(triphenylphosphine)palladium(0) (180 mg, 0.16 mmol)in degassed THF (10 mL). The resulting solution is stirred for 5 min. Asolution of phenylboronic acid (760 mg, 6.2 mmol) in THF (10 mL) isadded followed by aqueous Na₂CO₃ (2M, 5.2 mL). The mixture is heated atreflux for 24 h. The reaction mixture is allowed to cool, poured intoether, and washed twice with water. The ether layer is dried over Na₂SO₄and concentrated in vacuo. The crude product is purified by flash columnchromatography (1:1 hexanes:CH₂Cl₂) to yield5-phenylthiophene-2-carboxaldehyde (900 mg, 91%). ¹H NMR (300 MHz,CDCl₃) δ7.38-7.45, 7.65-7.68, 7.73, 9.88.

[0988] Step 3b

[0989] The product of Step 3a (750 mg, 4 mmol) is dissolved in a mixtureof THF, t-BuOH, and water (2:1:1, 60 mL). KH₂PO₄ (1.36 g, 10 mmol) isadded followed by NaClO₂ (900 mg, 10 mmol). The mixture is stirred at rtfor 5 days. Aqueous NaOH (2M, 10 mL) is added, and a majority of theorganic solvents are removed in vacuo yielding an aqueous suspension.This suspension is diluted with water and washed three times withCH₂Cl₂. The aqueous layer is acidified to pH<6 with 25% H₂SO4 and theproduct is extracted three times with CH₂Cl₂. The combined organicwashes are dried over Na₂SO₄, filtered and concentrated in vacuo toyield 5-phenylthiophene-2-carboxylic acid (417 mg, 51%). MS for C₁₁H₈O₂S(ESI) (M−H)⁻ m/z 203.

[0990] Step 3c

[0991] To a stirred solution of 5-phenylthiophene-2-carboxylic acid (100mg, 0.50 mmol) in dry DMF (10 mL) is added DIEA (265 μL, 1.5 mmol),followed by exo-(4S)-[2.2.1]-3-Amine (230 mg, 0.50 mmol). The solutionis cooled with an ice bath before 190 mg (0.50 mmol) of HATU is added.The solution is allowed to warm to rt and stir for 16 h. The solvent isremoved in vacuo, and the remaining residue is partitioned betweensaturated aqueous K₂CO₃ solution and 9:1 CHCl₃—MeOH. The aqueous layeris extracted with 9:1 CHCl₃—MeOH, and the combined organic layers arewashed with brine, dried over MgSO₄, filtered and concentrated in vacuoto afford the free base of Example 3 as a light yellow solid (150 mg,100%): MS for C₁₇H₁₈ON₂S (ESI) m/e 299 (M+H)⁺.

[0992] Step 3d

[0993] To a stirred solution of the product from Step 3c (150 mg, 0.50mmol) in MeOH (2 mL) is added a hot solution of fumaric acid (58 mg,0.50 mmol) in IPA (2 mL). The mixture is stirred for 30 min in a 50° C.water bath. The solvents are removed in vacuo and the remaining residueis dissolved in ether (5 mL). The mixture is stirred overnight at rt.The solid precipitate is collected by filtration and washed withacetone. The solid is dried in vacuo overnight to give 180 mg (87%) ofExample 3 as a white solid: ¹H NMR (CD₃OD) δ7.8, 7.7, 7.5-7.4, 6.7, 4.2,3.7-3.6, 3.5-3.3, 3.2, 3.0, 2.2-2.1, 1.8.

EXAMPLE 4

[0994]5-(2-Aminophenyl)-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-thiophene-2-carboxamide:

[0995]5-(2-Nitrophenyl)-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-thiophene-2-carboxamidecan be reduced to the amine applying H₂ under pressure in the presenceof Pd/C using EtOH and CH₂Cl₂ as the solvent to give Example 4.

EXAMPLE 5

[0996]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-pyridin-3-yl-thiophene-2-carboxamide:

[0997] Step 5a

[0998] In a flask are placed 3-pyridinediethylborane (0.81 g, 5.5 mmol),2-bromothiophene-5-carboxaldehyde (0.59 mL, 5.0 mmol), and Pd(PPh₃)₄(0.17 g, 0.15 mmol). The flask is vacuum purged and nitrogen filledthree times followed by addition of a 4:1 mixture of toluene-EtOH (8.3mL) by syringe. After careful vacuum purge/nitrogen fill (3X), asolution of Na₂CO₃ (2M, 5 mL, 10.0 mmol) is added by syringe, and theflask is vacuum purged and nitrogen filled (3X). The reaction mixture isheated to 90° C. and stirred for 22 h. The reaction mixture is cooled tort and diluted with H₂O. The aqueous solution is extracted with ether(3X). The combined ether layers are then washed with water (3X) andbrine (2X). The organic layer is dried over MgSO₄, diluted with EtOAcfor solubility, then filtered and concentrated. The crude product isthen chromatographed over silica gel (10/30/50% EtOAc-heptane gradient)to provide 5-(3-pyridinyl)-2-thiophenecarboxaldehyde as a yellow solid(0.34 g, 35%). ¹NMR (400 MHz, CDCl₃): 9.97, 9.05, 8.68, 8.13, 7.83,7.59-7.54.

[0999] Example 5 can be made from the product of Step 5a by using theprocedure discussed in Steps 3b and 3c, making non-critical variations.

EXAMPLE 6

[1000]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5′-methyl-2,2′-bithiophene-5-carboxamide:

[1001] Step 6a

[1002] In a flask are placed 2-bromothiophene-5-carboxylic acid (1.20 g,5.81 mmol), 5-methylthiophene-2-boronic acid (0.99 g, 6.97 mmol), andPd(PPh₃)₄ (0.20 g, 0.17 mmol). The flask is then vacuum purged andnitrogen filled (3X). THF (12 mL) is then added by syringe followed byvacuum purge and nitrogen fill (3X). A solution of Na₂CO₃ (2M, 5.8 mL,11.6 mmol) is added followed by vacuum purge and nitrogen fill (3X). Thereaction mixture is heated to reflux for 19 h then cooled to rt anddiluted with water. The aqueous solution is extracted with ether (3X).The aqueous layer is then acidified and extracted with EtOAc (3X). Thecombined organic layers are dried over MgSO₄, filtered, and concentratedto provide an inseparable 3:1 mixture of 2-bromothiophene-5-carboxylicacid and bithiophene product. To separate the compounds the methylesters are formed: In a flask are placed the aforementioned mixture,MeOH (50 mL) and conc H₂SO₄ (5 drops) and heated to reflux for 24 h. Thesolution is concentrated and chromatographed over silica gel (2%acetone-heptane) to provide methyl5′-methyl-2,2′-bithiophene-5-carboxylate as a solid (0.37 g, 26% 2steps). ¹H NMR (400 MHz, CDCl₃) δ7.69, 7.10, 7.07, 6.73, 3.91, 2.52.

[1003] Step 6b

[1004] The product of Step 6a (0.37 g, 1.54 mmol), dioxane (5 mL) andLiOH (1N, 3.1 mL, 3.1 mmol) are placed in a flask. Additional dioxane (5mL) is then added for solubility and stirred for 24 h at rt. 1N HCl isadded slowly until pH<6, whereupon a precipitate forms. The precipitateis then collected by filtration, rinsed with water, and dried in a 70°C. vacuum oven to provide 5′-methyl-2,2′-bithiophene-5-carboxylic acidas a yellow solid (0.30 g, 86%). MS for C₁₀H₈O₂S₂ (ESI) (M−H)⁻ m/z 223.

[1005] Example 6 can be made using the product of Step 6b as thestarting material and using the procedure discussed in either Step 1a orStep 2a, making non-critical variations.

EXAMPLE 7

[1006]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5′-chloro-2,2′-bithiophene-5-carboxamide:

[1007] Step 7a

[1008] In a flask are placed 2-bromo-5-chlorothiophene (0.55 mL, 5.0mmol) and Pd(PPh₃)₄ (0.17 g, 0.15 mmol), and the flask is vacuum purgedand nitrogen filled (3X). THF (10 mL) is added by syringe and stirred 10min. In a separate flask is placed 5-formyl-2-thiopheneboronic acid(0.94 g, 6.0 mmol) and EtOH (2 mL) and stirred until dissolved. Thismixture is added by syringe to the first flask followed by vacuum purgeand nitrogen fill (3X). A solution of Na₂CO₃ (2M, 5.0 mL, 10.0 mmol) isadded by syringe followed by vacuum purge and nitrogen fill (3X). Thereaction mixture is heated at 85° C. for 20 h. The reaction is cooled tort and diluted with water. The aqueous solution is extracted with ether(3X). The combined ether layers are washed with water (3X) then brine(2X). The ether is dried over MgSO₄, filtered, and concentrated. Thecrude product is purified over silica gel (5% EtOAc-heptane) to provide5′-chloro-2,2′-bithiophene-5-carboxaldehyde as an orange solid (0.27 g,24%). ¹H NMR (400 MHz, CDCl₃) δ9.89, 7.69, 7.20, 7.16, 6.93.

[1009] Example 7 can be made from the product of Step 7a as the startingmaterial by using the procedures discussed in Steps 3b and 3c, makingnon-critical variations.

EXAMPLE 8

[1010]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-nitro-thiophene-2-carboxamide:

[1011] Example 8 can be made from 2-nitrothiophene-5-carboxaldehyde byusing the procedure discussed in Steps 3b and 3c, making non-criticalvariations.

Example 9

[1012]5-(Aminomethyl)-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-thiophene-2-carboxamide:

[1013] Step 9a

[1014] A 500 mL receiving flask is placed in an ice bath, and to theflask is added thiophene-2-methylamine (5.0 mL, 48.7 mmol), CH₂Cl₂ (250mL) then di-tert-butyl dicarbonate (12.7 g, 73.0 mmol) in 2-3 g portionsover 5 min. The reaction mixture is stirred for 3 h then washed with 1NHCl (3X), 1N NaOH (3X) and brine (2X). The organic layer is dried overMgSO₄, filtered and concentrated to a yellow oil. The oil ischromatographed over silica gel (2.5-5% EtOAc-heptane gradient) toprovide 8.70 g (84%) of tert-butyl 2-thienylmethylcarbamate as a clearoil. MS for C₁₀H₁₅NO₂S (ESI) (M+H)⁺ m/z 214.

[1015] Step 9b

[1016] In a flask is placed the product of Step 9a (3.50 g, 16.4 mmol)and dry THF (80 mL) then cooled in an acetone/solid CO₂ bath. Lithiumdiisopropylamide (18.0 mL, 36.1 mmol, 2.0M solution inheptane/THF/ethylbenzene) is added in a slow stream by syringe. Theresulting orange solution is stirred for 10 min and then quenched withexcess dry ice. The solution is warmed over 1 h and the THF removed invacuo. The crude product is diluted with CH₂Cl₂ and washed with 1N HCl(3X). The CH₂Cl₂ is removed in vacuo and replaced with EtOAc due toinsolubility. The organic solution is dried over MgSO₄, filtered, andconcentrated to provide a dark orange oil, which is chromatographed oversilica gel (25-90% EtOAc-heptane gradient) to provide 0.873 g (21%) of5-([(tert-butoxycarbonyl)amino]methyl)-2-thiophenecarboxylic acid as anoff-white foam. ¹H NMR (400 MHz, CDCl₃) δ12.96, 7.60, 7.56, 6.97, 4.28,1.40.

[1017] Example 9 can be made by using the product of Step 9b as astarting material and using the procedure discussed in either Step 1a orStep 2a, making non-critical variations.

EXAMPLE 10

[1018]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-cyano-thiophene-2-carboxamide:

[1019] Step 10a

[1020] In a 500 mL receiving flask are placed thiophene-2-carbonitrile(5.0 mL, 53.8 mmol) and THF (270 mL) and cooled in an acetone/solid CO₂bath. Lithium diisopropylamide (40.3 mL, 80.7 mmol, 2.0M solution inheptane/THF/ethylbenzene) is added in a slow stream via syringe. Thesolution is stirred for 10 min then quenched with an excess of dry ice.The reaction mixture is warmed in a water bath and the THF removed invacuo. The slurry is taken up in 1N NaOH and extracted with ether (3X).The aqueous layer is then acidified to pH<6 with conc. HCl, whereupon abrown precipitate forms. This precipitate is filtered off and to theresulting eluent is added 1N HCl which results in precipitation of theproduct. The product is collected by filtration then triturated withCH₂Cl₂. Purification over silica gel (1:2.5:100 formic acid:MeOH:CH₂Cl₂)provides 5-cyano-thiophene-2-carboxylic acid as a solid (1.79 g, 22%).¹H NMR (400 MHz, CDCl₃) δ14.10, 8.00, 7.80.

[1021] Example 10 can be made by using the product of Step 10a as astarting material and using the procedure discussed in either Step 1a orStep 2a, making non-critical variations.

Example 11

[1022]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(pyridin-2-yl)-thiophene-2-carboxamide.fumarate:

[1023] Following the procedure of Step 3c from Example 3, the free baseof Example 11 is obtained in quantitative yield as a light yellow solid:MS for C₁₆H₁₇ON₃S (ESI) m/e 300 (M+H)⁺.

[1024] Following the procedure of Step 3d from Example 3, Example 11 isobtained in 84% yield as a white solid: ¹H NMR (CD₃OD) δ8.5, 7.9, 7.8,7.7, 7.4, 6.7, 4.2, 3.7, 3.4-3.3, 3.2, 3.0, 2.2-2.1, 1.8.

EXAMPLE 12

[1025]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylthiazol-4-yl)-thiophene-2-carboxamide:

[1026] Step 12a

[1027] Aqueous LiOH (1N, 1.5 mL) is added to a solution of methyl5-(2-methylthiazol-4-yl)-thiophene-2-carboxylate (81 mg, 0.34 mmol) indioxane (1 mL). The reaction is stirred at rt for 2 hr. Aqueous HCl (1N,4 mL) is added and the resultant precipitate is collected by filtration,washed with water, and dried to give5-(2-methylthiazol-4-yl)-thiophene-2-carboxylic acid (53 mg, 69%). ¹HNMR (300 MHz, DMSO-d₆) δ8.03, 7.69, 7.59, 2.70.

[1028] Example 12 can be made by using the product of Step 12a as astarting material and using the procedure outlined for Example 1 orExample 2, making non-critical variations.

EXAMPLE 13

[1029]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-[2-(3-chlorophenyl)-vinyl]-thiophene-2-carboxamide:

[1030] Example 13 can be prepared from methyl 5-[2-(3-chlorophenyl)vinyl]-thiophene-2-carboxylate according to the procedure used to makethe compound of Example 12, making non-critical variations.

EXAMPLE 14

[1031]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-chlorophenylsulfanyl)-thiophene-2-carboxamide:

[1032] Step 14a

[1033] Sodium hydride (60%, 1.2 g, 30 mmol) is added to a solution of4-chlorothiophenol (4.3 g, 30 mmol) in THF (30 mL). The resultingsolution is stirred for 10 min then the solvent is removed in vacuo.Acetone (60 mL) is added followed by 5-bromothiophene-2-carboxaldehyde(30 mL, 25 mmol). The mixture is stirred at rt for 2 hr. The solvent isremoved in vacuo and the resulting slurry diluted with CH₂Cl₂. Thissolution is washed three times with 1N NaOH then dried over MgSO₄,filtered and concentrated in vacuo. The crude product is purified byflash column chromatography (gradient of 1 to 5% EtOAc in heptane) togive 5-(4-chlorophenylsulfanyl)-thiophene-2-carboxaldehyde (6.2 g, 98%).¹H NMR (300 MHz, CDCl₃) δ7.13, 7.31-7.39, 7.63, 9.78.

[1034] Step 14b

[1035] The product of Step 14a (6.1 g, 24 mmol) is dissolved in amixture of THF, t-BuOH, and water (3:3:1, 255 mL). 2-Methyl-2-butene(20.3 mL, 192 mmol) is added followed by KH₂PO₄ (9.8 g, 72 mmol) andthen NaClO₂ (80%, 8.17 g, 72.3 mmol). The mixture is stirred at rt for 2hr. Aqueous KHSO₄ (0.5M, 200 mL) is added and the organic solvents areremoved in vacuo to produce an aqueous suspension of the product. Theprecipitate is collected by filtration, dissolved in 1N NaOH and washedtwo times with ether. The aqueous solution is then acidified to pH<6with concentrated HCl and a precipitate formed. The precipitate iscollected by filtration and washed with 0.5M KHSO₄ then water. The solidis dried in vacuo to give5-(4-chlorophenylsulfanyl)-thiophene-2-carboxylic acid (5.7 g, 87%). MSfor C₁₁H₇ClO₂S₂ (ESI) (M−H)⁻ m/z 269.

[1036] Step 14c

[1037] Example 14 can be obtained using the coupling proceduresdiscussed herein. The salt can be obtained as discussed herein.

EXAMPLE 15

[1038]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-phenoxy-thiophene-2-carboxamide:

[1039] Step 15a

[1040] Phenol (3.3 g, 35 mmol) is added in portions to a suspension of60% NaH (1.3 g, 35 mmol) in DMSO (100 mL). The resulting mixture isstirred for 30 min then 5-nitrothiophene-2-carboxaldehyde (5 g, 32 mmol)is added. After 1 hr the reaction mixture is poured into water (1L) andwashed with ether (4×500 mL). The combined organic layers are dried overNa₂SO₄, filtered and evaporated to dryness. The resulting material isdissolved in MeOH and passed through a column (2.5 cm×20 cm) of Amberjet4400 (OH⁻ form). The eluent is dried in vacuo then evaporated twice fromCH₃CN. The crude product is purified by column chromatography inEtOAc-hexanes (1:1) to yield 5-phenoxy-thiophene-2-carboxaldehyde (304mg, 5%). ¹H NMR (300 MHz, CDCl₃) δ6.52, 7.20, 7.27, 7.45, 7.55, 9.75.

[1041] Step 15b

[1042] 5-Phenoxy-thiophene-2-carboxaldehyde (325 mg, 1.6 mmol) isdissolved in a mixture of THF (10 mL), t-BuOH (5 mL) and water (5 mL).NaH₂PO₄ (650 mg, 4.8 mmol) is added followed by NaClO₂ (432 mg, 4.8mmol). The resulting mixture is stirred for 24 hr at rt. Aqueous NaOH(2M, 5 mL) is added, and the organic solvents are removed in vacuo. Theresulting aqueous suspension is poured into water (50 mL) and washedwith ether (3×50 mL). The aqueous layer is acidified to pH<2 with 25%H₂SO₄ then washed with CH₂Cl₂ (3×50 mL). The combined organic washes aredried over Na₂SO₄, filtered and concentrated in vacuo. The crude productis dissolved in hot aqueous acetone and filtered. The solvents aregradually removed until a precipitate forms. The solid is collected byfiltration and dried in vacuo to yield 5-phenoxy-thiophene-2-carboxylicacid (192 mg, 55%). MS for C₁₁H₇O₃S (ESI) (M+H)⁺ m/z 219.

[1043] Example 15 can be made according to the procedures discussedherein, starting with 5-phenoxy-thiophene-2-carboxylic acid and makingnon-critical variations.

EXAMPLE 16

[1044]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)-thiophene-2-carboxamide:

[1045] Step 16a

[1046] Tetrakis(triphenylphosphine)palladium(0) (133 mg, 0.12 mmol) isadded to a solution of 5-bromothiophene-2-carboxylic acid (850 mg, 4.6mmol) in degassed THF (10 mL). The resulting solution is stirred for 5min and then 2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl) phenol (1g, 4.6 mmol) is added followed by aqueous Na₂CO₃ (2M, 6.9 mL). Themixture is heated at reflux overnight. The reaction mixture is allowedto cool, poured into water (50 mL), and washed with ether (3×50 mL). Theaqueous layer is acidified with concentrated HCl to pH<2. The resultingprecipitate is collected by filtration, washed with water and dried invacuo to yield 5-(2-hydroxyphenyl)-thiophene-2-carboxylic acid (761 mg,83%). MS for C₁₁H₇O₃S (ESI) (M−H)⁺ m/z 219.

[1047] Example 16 can be obtained using the coupling methods discussedherein.

EXAMPLE 17

[1048]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)-thiophene-2-carboxamide:

[1049] Example 17 can be made from the 3-hydroxyphenylboronic acidaccording to the procedure of Example 16, making non-criticalvariations.

EXAMPLE 18

[1050]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluoro-4-hydroxyphenyl)-thiophene-2-carboxamide:

[1051] Step 18a

[1052] Example 18 can be obtained by starting fromN-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-benzyloxyphenyl)-thiophene-2-carboxamide,which can be obtained following the procedures outlined for Example 3using 3-benzyloxyphenylboronic acid as the acid. The intermediate canthen be dissolved in MeOH and poured through a plug of Amberjet 4400(OH⁻ form). The solvent can be removed in vacuo, and the product can beredisolved in EtOH. This solution can be added to a suspension of 10%Pd/C in EtOH. Cyclohexadiene (360 mL, 3.8 mmol) would be added, and thereaction heated at 60° C. for 6 hr. The reaction mixture can then bediluted with MeOH and filtered through celite. The solvents can beremoved in vacuo to give the free base. A salt can be formed asdiscussed herein.

EXAMPLE 19

[1053]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(phenylsulfanyl)-1,3-thiazole-5-carboxamide:

[1054] Step 19a

[1055] A suspension of ethyl 2-bromo-1,3-thiazole-5-carboxylate (1.5 g,6.15 mmol, 1 eq) and K₂CO₃ (1.7 g, 12.3 mmol, 2 eq) in EtOH (60 mL) iscooled in an ice bath, and thiophenol (0.631 mL, 6.15 mmol, 1 eq) isadded. The reaction is monitored by HPLC until the starting material isconsumed. The reaction mixture is filtered (to remove a solidby-product), and the solvent is removed in vacuo. The crude mixture ispurified by silica gel chromatography using a Biotage Flash 40S columnusing 2% EtOAc in hexanes to afford ethyl2-phenylsulfanyl-thiazole-5-carboxylate as an oil (0.784 g, 46%). MS(ESI) for C₁₂H₁₁NO₂S₂ m/z 266.1 (M+H)⁺.

[1056] Step 19b

[1057] Potassium hydroxide (1.58 g, 28.2 mmol, 10 eq) is added to asolution of the product from Step 45a (0.748 g, 2.82 mmol, 1 eq) in EtOH(15 mL) and water (10.5 mL). The reaction is stirred for 1.5 hr, dilutedwith water (30 mL) and EtOH (30 mL), and acidified by addition of 3 NHCl until a white precipitate forms. The precipitate is filtered andpurified by recrystallization from water and EtOH to give2-phenylsulfanyl-thiazole-5-carboxylic acid as a white crystalline solid(0.307 g). MS (ESI) for C₁₀H₇NO₂S₂ m/z 235.9 (M−H)⁻.

[1058] Example 19 can be obtained using the coupling methods discussedherein.

EXAMPLE 20

[1059]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-phenyl-1,3-thiazole-5-carboxamide:

[1060] Step 20a

[1061] A solution of α-formyl-α-chloroacetate (9.34 g, 49.5 mmol, 1 eq)and thiobenzamide (6.79 g, 49.5 mmol, 1 eq) in EtOH (37.0 mL) isrefluxed for 1 hr. The solution changes from an orange/brown color to adeep green. This solution is washed with water and extracted withCH₂Cl₂. The organic fraction is dried over Na₂SO₄, filtered, and thesolvent removed in vacuo. The product is purified by columnchromatography using a Biotage Flash 40M column (20% hexanes/EtOAc) togive ethyl 2-phenyl-thiazole-5-carboxylate as a deep orange oil (1.82 g,15%). MS (ESI) for C₁₂H₁₃NO₃S m/z 252.1 (M+H)⁺.

[1062] Making non-critical variations, Example 20 can be prepared usingprocedures discussed for Example 19.

EXAMPLE 21

[1063]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(2-fluorophenyl)-1,3-thiazole-5-carboxamide:

[1064] Step 21a

[1065] Tetrakis(triphenylphosphine)palladium (0) (0.58 g, 0.5 mmol), anda degassed solution of 2.0M Na₂CO₃ (10 mL) are added to a degassedsolution of ethyl 2-bromo-1,3-thiazole-5-carboxylate (1.18 g, 5.0 mmol)and 2-fluorophenylboronic acid (0.77 g, 5.5 mmol) in DME (10 mL). Theresulting suspension is stirred under argon at 80° C. for 4 hr. Thereaction mixture is cooled, diluted with EtOAc, and then washed with twoportions of 1.0 M NaOH, then one portion of brine. The combined organicphases are concentrated in vacuo, and the resulting oil purified withflash chromatography to give ethyl2-(2-fluorophenyl)-1,3-thiazole-5-carboxylate. Yield 37%. HRMS (FAB)calculated for C₁₂H₁₀FNO₂S+H 252.0495, found 252.0496.

[1066] Example 21 can be obtained by hydrolyzing the product from Step21a and coupling using procedures discussed herein.

EXAMPLE 22

[1067]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(methylamino)-1,3-thiazole-5-carboxamide:

[1068] Step 22a

[1069] A flask is charged with a solution of ethyl2-amino-1,3-thiazole-5-carboxylate (2.65 g, 15.4 mmol) and4-dimethylaminopyridine (10 mg) in THF (75 mL). Di-(tert-butyl)dicarbonate (3.6 mL, 15.4 mmol,1.0 eq) and TEA (4.3 mL, 30.8 2.0 eq) areadded, and the resulting solution is stirred at rt for 90 min. Thereaction mixture is concentrated to dryness, and the crude product iscrystallized from CHCl₃/hexanes to give ethyl2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate as a lightbrown solid. Yield 68%. HRMS (FAB) calculated for C₁₁H₁₆N₂O₄S+H273.0909, found 273.0897.

[1070] Step 22b

[1071] A flask is charged with a suspension of sodium hydride (60% inmineral oil) (0.109 g, 2.72 mmol) in THF (5 mL). The ethyl2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate (0.735 g, 2.70mmol) is added, followed by iodomethane (175 μL, 2.70 mmol) and theresulting suspension is heated to reflux for 3 hr, then cooled to rt.Water is added, followed by 1.0 N NaOH. The basic phase is extractedwith 3 portions of EtOAc. The combined organic phases are washed withbrine, dried over Na₂SO₄, filtered, and concentrated to give a clear oilpurified with flash chromatography to give ethyl2-[(tert-butoxycarbonyl)(methyl)amino]-1,3-thiazole-5-carboxylate. Yield45%. HRMS (FAB) calculated for C₁₂H₁₈N₂O₄S+H 287.1065, found 287.1068.

[1072] Step 22c

[1073] The product of Step 22b is hydrolyzed according to Step 19b,making non-critical variations to give2-[(tert-butoxycarbonyl)(methyl)amino]-1,3-thiazole-5-carboxylic acid.Yield 49%. HRMS (FAB) calculated for C₁₀H₁₄N₂O₄S+H 259.0752, found259.0750.

[1074] Step 22d

[1075] The product of Step 22c can be coupled according to Step 19c. Thecitrate can be prepared from the crude reaction mixture withoutchromatography, and crystallized until tert-butyl5-([1-azabicyclo[2.2.1]oct-3-ylamino]carbonyl)-1,3-thiazol-2-yl(methyl)carbamateis of analytical purity.

[1076] Example 22 can be obtained by treating the product from Step 22dwith a solution of 4.0N HCl/dioxane. The product can be crystallizedfrom IPA/ether.

EXAMPLE 23

[1077]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide:

[1078] Step 23a

[1079] A mixture of 3-chlorophenylacyl bromide (5.18 g, 22.2 mmol, 1eq), sodium diformylimide (2.11 g, 22.2 mmol, 1 eq) and CH₃CN (125 mL)is heated in an 80° C. oil bath. After 3.5 h, the mixture is filteredand evaporated. The residue is treated with EtOH (40 mL) and HCl (10 mL,12 N). The mixture was then heated in a 50° C. water bath for 30 min andevaporated. The resulting solid is triturated with acetone and collectedby filtration to afford 2-amino-1-(3-chlorophenyl)ethanone hydrochloride(2.86 g, 62%). MS (ESI) for C₈H₈ClNO m/z 170 (M+H)⁺.

[1080] Step 23b

[1081] A mixture of the product from Step 23a (2.83 g, 13.7 mmol, 1 eq),ethyl chlorooxoacetate (1.87 g, 13.7 mmol, 1 eq), and CH₂Cl₂ (40 mL) iscooled in an ice-H₂O bath. The mixture is treated with a solution of TEA(4.0 mL, 29 mmol, 2.1 eq) in CH₂Cl₂ (20 mL), and the reaction is warmedto rt overnight. Water is added and the organic layer is separated,dried over MgSO₄, filtered, and evaporated. The resulting solid istriturated with hexane/2-propanol and dried in vacuo to provide ethyl[[2-(3-chlorophenyl)-2-oxoethyl]amino](oxo) (2.70 g, 72%). MS (ESI) forC₁₂H₁₂ClNO₄ m/z 270 (M+H)⁺.

[1082] Step 23c

[1083] A mixture of the product from Step 23b (1.28 g, 4.70 mmol, 1 eq),benzene (8 mL), and POCl₃ (2.0 mL, 21 mmol) is heated under reflux for65 h and cooled. The mixture is then evaporated and extracted betweenCHCl₃ and water. The organic layer is separated, dried over MgSO₄,filtered, and evaporated. The residue is crystallized from EtOH to giveethyl 5-(3-chlorophenyl)-1,3-oxazole-2-carboxylate (0.61 g, 51%). MS(ESI) for C₁₂H₁₀ClNO₃ m/z 252 (M+H)⁺.

[1084] Example 23 can be obtained using coupling procedures discussedherein.

EXAMPLE 24

[1085]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-4-methyl-5-phenyl-1,3-thiazole-2-carboxamide:

[1086] Step 24a 2-Bromo-1-phenylpropan-1-one (8.97 g, 42.1 mmol, 1 eq)is added dropwise to a suspension of diformylimide sodium salt (4.80 g,50.5 mmol, 1.2 eq) in 80 mL CH₃CN. The reaction is stirred for 60 h at70-75° C. The hot mixture is filtered to remove the salts and the solidsare washed with CH₃CN. The combined filtrates are concentrated in vacuo,dissolved in 40 mL 6N HCl and heated under reflux for 0.75 h. Thesolvents are removed under reduced pressure and the product isrecrystallized from IPA to give 2-amino-1-phenylpropan-1-onehydrochloride (6.15 g, 79%). MS (ESI) for C₉H₁₁NO m/z 150.2 (M+H)⁺.

[1087] Step 24b

[1088] TEA (3.22 mL, 0.0231mol, 2.1 eq) is added dropwise to asuspension of the product from Step 24a (2.05 g, 11.0 mmol, 1 eq) andethyl oxalyl chloride (1.24 mL, 11.0 mmol, 1 eq) in 50 mL CH₂Cl₂ in anice/water bath. The mixture is allowed to slowly warm to rt. Afterstirring overnight, water and 20 mL 1N HCl are added. The aqueous layeris extracted with CH₂Cl₂. The combined organic layers are dried overMgSO₄, filtered and concentrated to give ethyl[(1-methyl-2-oxo-2-phenylethyl)amino](oxo)acetate as a yellow oil (2.58g, 94%). MS (ESI) for C₁₃H₁₅NO₄ m/z 250.2 (M+H)⁺.

[1089] Step 24c

[1090] The product from Step 24b (2.58 g, 10.4 mmol, 1 eq) and P₂S₅(4.83 g, 10.9 mmol, 1.05 eq) are suspended in 30 mL CHCl₃. The mixtureis heated under reflux. After 12 h, water and solid K₂CO₃ are carefullyadded until all material dissolves. The aqueous layer is madesufficiently basic with 1N NaOH (pH more than 10) and extracted withEtOAc. The combined organic layers are washed with 1N NaOH and brine,dried over MgSO₄, filtered and concentrated to give ethyl4-methyl-5-phenyl-1,3-thiazole-2-carboxylate as a yellow oil (2.51 g,98%). MS (ESI) for C₁₃H₁₃NO₂S m/z 248.1 (M+H)⁺.

[1091] Example 24 can be obtained using coupling methods discussedherein.

EXAMPLE 25

[1092]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-furan-2-carboxamide.fumarate:

[1093] Step 25a

[1094] A solution of 5-bromo-furan-2-carbaldehyde (1.08 g, 6.16 mmol, 1eq), phenylboronic acid (0.90 g, 7.39 mmol, 1.1 eq), tetrabutylammoniumbromide (1.99 g, 6.16 mmol, 1 eq), palladium acetate (30 mg, 0.0.12 mmol0.02 eq), K₂CO₃ (2.13 g, 15.4 mmol, 2.5 eq) in water (10 mL) is stirredunder nitrogen at rt overnight. The reaction is diluted with 40 mL waterand extracted with EtOAc (3×100 mL). The organic layers are combined andstirred with charcoal for 30 min, then dried over MgSO₄ and filtered.The solvent is removed under reduced pressure to give5-phenyl-furan-2-carbaldehyde as an oil. The product is purified bysilica gel chromatography using a Biotage Flash 40M column (10%EtOAc/heptane).

[1095] Step 25b

[1096] To a solution of the product from Step 25a (0.650 g, 3.78 mmol, 1eq) in water (5.5 mL), t-BuOH (18.0 mL), and THF (18.0 mL) is added2-methyl-2-butene (3.2 mL, 30.2 mmol, 8 eq), potassium phosphatemonobasic (1.54 g, 11.3 mmol, 3 eq), then NaClO₂ (1.03 g, 11.3 mmol, 3eq) in that order. After 4 hr, the reaction is complete and diluted with1 N NaOH (100 mL). The aqueous solution is extracted with ether (2×100mL), and the aqueous layer is acidified with conc. HCl. The resultingsolution is extracted with CH₂Cl₂ (3×100 mL). The organic layers aredried over MgSO₄, and the solvent removed. 5-Phenyl-furan-2-carboxylicacid is purified by silica gel chromatography using a Biotage Flash 40Mcolumn (10% EtOAc/1% formic acid/heptane). The solid remaining afterremoval of the solvent is filtered and recrystallized from EtOH andwater to give the acid as a white crystalline solid (0.499 g, 70.2%).HRMS (FAB) calculated for C₁₁H₈O₃+H 189.0473, found 189.0403.

[1097] Following the procedure of Step 3c, the free base of Example 25is obtained in quantitative yield as a light yellow solid: MS (ESI) m/e283 [M+H].

[1098] Following the procedure of

[1099] Step 3d, Example 25 is obtained in 80% yield as a white solid: ¹HNMR (DMSO-d₆) δ8.3, 7.9, 7.5, 7.4, 7.2, 7.1, 6.5, 3.8, 3.1, 3.0-2.8,2.7-2.6, 1.8-1.7, 1.3.

[1100] The following examples are prepared from the requisite boronicacid, furaldehyde, or furan-carboxylic acid according to the proceduresfor Example 25, making non-critical variations.

EXAMPLE 26

[1101]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)-furan-2-carboxamide.fumarate(from 2-fluorophenylboronic acid). ¹H NMR (DMSO-d₆) δ8.4, 8.1, 7.5-7.4,7.3, 7.0, 6.6, 3.8, 3.1, 3.0-2.8, 2.6, 1.8-1.7, 1.3.

EXAMPLE 27

[1102]N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)-furan-2-carboxamide(from 3-fluorophenylboronic acid). The yield for the coupling andobtaining the salt is 62.5%. ¹H NMR (400 MHz, CD₃OD): 7.96-7.92, 7.26,7.24-7.20, 6.93, 6.71, 4.23, 3.66, 3.45-3.35, 3.21-3.18, 3.06, 2.16,1.82.

EXAMPLE 28

[1103]N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)-furan-2-carboxamide(from 4-fluorophenylboronic acid). The yield for the coupling andobtaining the salt is 50%. ¹H NMR (400 MHz. CD₃OD): 7.74-7.70, 7.48,7.28, 7.13, 7.04, 6.71, 4.28, 3.72, 3.52-3.38, 3.27-3.25, 3.08, 2.20,1.80.

EXAMPLE 29

[1104]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(2,3-difluorophenyl)-furan-2-carboxamide:

[1105] Example 29 can be obtained in the following way:N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-furan-2-carboxamide (1eq), 2,3-difluorophenylboronic acid (1.1 eq), and tetrabutylammoniumbromide (1 eq), palladium acetate (0.02 eq), K₂CO₃ (3.5 eq) are stirredin an amount of water to afford about a 0.6M concentration of thecarboxamide. The reaction is stirred under argon overnight. The reactionis purified by silica gel chromatography using a Biotage Flash system.

[1106] Example 30 is prepared from the requisite boronic acid andN-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-furan-2-carboxamide,making non-critical variations:

EXAMPLE 30

[1107]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)-furan-2-carboxamide.fumarate(from p-tolylboronic acid). ¹H NMR (DMSO-d₆) δ6 8.3, 7.8, 7.3, 7.2, 7.0,6.6, 3.8, 3.2-3.1, 3.0-2.8, 2.7, 2.3, 1.8-1.7, 1.3.

EXAMPLE 31

[1108]5-(2-Aminophenyl)-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-furan-2-carboxamide:

[1109] Example 31 can be prepared by the following: To a solution ofN-[1-aza-bicyclo[2.2.1]oct-3-yl]-5-(2-nitro-phenyl)-furan-2-carboxamidein was added Pd/C (10 mol %). This mixture was placed on a Parr shakerunder 40 psi hydrogen until starting material is consumed. The palladiumis removed by filtration over a pad of celite, and the solvent isremoved.

EXAMPLE 32

[1110]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-(phenylethynyl)-furan-2-carboxamide:

[1111] Step 32a

[1112] To a solution of 5-bromofuraldehyde (1.0 g, 5.71 mmol, 1 eq),copper (I) iodide (0.163 g, 0.857 mmol, 0.15 eq),trans-dichlorobis(triphenylphosphine) palladium(II) (0.20 g, 0.287 mmol,0.05 eq), and TEA (3.98 mL, 28.6 mmol, 5 eq) in THF (45 mL) is addeddropwise phenyl acetylene (1.25 mL, 11.4 mmol, 2 eq). After 48 hr, thereaction appears complete. The reaction is filtered over a pad ofcelite, and the solvent is removed under reduced pressure. The reactionis purified by silica gel chromatography using a Biotage Flash 40Mcolumn (10% EtOAc/heptane) to give 5-phenylethynyl-furan-2-aldehyde as ayellow orange crystalline solid (0.765 g, 68.3%). MS (ESI) for C₁₃H₈O₂m/z 197.1 (M+H)⁺.

[1113] Following the general procedure of Example 25, makingnon-critical variations but starting with5-phenylethylnyl-furan-2-aldehyde, Example 32 can be synthesized.

EXAMPLE 33

[1114]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-phenoxy-furan-2-carboxamide:

[1115] Example 33 can be obtained as follows: A solution ofN-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-furan-2-carboxamide (1eq), sodium phenoxide (10.1 eq), in DMSO (for about 1.0 M solution ofthe carboxamide) is stirred under nitrogen at rt overnight. The reactionis diluted with water and extracted with CH₂Cl₂. The organic layer iswashed with water, satd NaHCO₃, brine, and dried over MgSO₄ to affordthe desired product.

EXAMPLE 34

[1116]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-1-methyl-5-phenyl-1H-pyrrole-2-carboxamide:

[1117] Step 34a

[1118] To a dry flask is added methyl 1-methyl-1H-pyrrole-2-carboxylate(12.0 g, 86.4 mmol) and 150 mL of dry CH₂Cl₂, and the flask is wrappedin foil and purged with nitrogen. N-Bromosuccinimide (16.2 g, 90.7 mmol)is added in one portion and the mixture is stirred at rt for 0.5 h. Thereaction mixture is washed with water (50 mL) and brine (50 mL), driedover MgSO₄, filtered, and concentrated under reduced pressure.Fractional distillation gives 12.0 g of methyl5-bromo-1-methyl-1H-pyrrole-2-carboxylate as a yellow oil (64% yield).MS for C₇H₈NO₂Br (ESI) (M)+m/z 217.1.

[1119] Step 34b

[1120] The product from step 34a is added to a solution oftetrakis(triphenylphosphine)palladium(0) (0.530 g, 0.459 mmol) in 90 mLof ethylene glycol dimethyl ether. The resulting solution is stirredunder nitrogen for 5 min and then phenylboronic acid (1.34 g, 11.0 mmol)is added followed by a solution of Na₂CO₃ (19.5 g, 183 mmol) in 90 mL ofH₂O. The mixture is heated at reflux for 24 hr. The reaction mixture isallowed to cool to rt, 100 mL of CH₂Cl₂ is added, and the layers areseparated. The aqueous layer is extracted with CH₂Cl₂ (3×50 mL) andcombined organic layers are dried over MgSO₄, filtered, and concentratedin vacuo. The crude product is purified by flash column chromatography(5% EtOAc in hexane) to give 1.89 g of methyl1-methyl-5-phenyl-1H-pyrrole-2-carboxylate as a yellow oil (96% yield).MS for C₁₃H₁₃NO₂ (ESI) (M+H)⁺ m/z 216.1.

[1121] Step 152c

[1122] Lithium hydroxide (1.39 g, 33.2 mmol) is added to a solution ofthe product from Step 34b (1.43 g, 6.64 mmol) in 96 mL of a 1.25:1:1H₂O:MeOH:THF solvent mixture. The reaction is stirred at 50° C. for 2 h.Aqueous HCl (1N, 50 mL) is added and the resultant precipitate iscollected by filtration, washed with water, and dried to give 0.851 g of1-methyl-5-phenyl-1H-pyrrole-2-carboxylic acid as a tan solid (64%yield). MS for C₁₂H₁₁NO₂ (ESI) (M−H)⁺ m/z 200.1.

[1123] Example 34 can be obtained using coupling procedures discussedherein.

EXAMPLE 35

[1124]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide.fumarate:

[1125] Step 35a

[1126] To a stirred solution of 120 mg (0.63 mmol) of5-phenyl-1,3-oxazole-2-carboxylic acid (see: Saito, S.; Tanaka, C., J.Pharm. Sci. Japan, 76, 1956, 305-7) in dry DMF (10 mL) is added DIEA(2.33 mL, 1.34 mmol), followed by exo-4(S)-[2.2.1]-3-Amine (200 mg, 0.44mmol). The solution is cooled with an ice bath before 167 mg (0.44 mmol)of HATU is added. The solution is allowed to warm to rt and stir for 16h. The solvent is removed in vacuo, and the remaining residue ispartitioned between saturated aqueous K₂CO₃ solution and 9:1 CHCl₃—MeOH.The aqueous layer is extracted with 9:1 CHCl₃—MeOH, and the combinedorganic layers are washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to afford the free base of Example 35 as a lightyellow solid (91 mg, 73%): MS for C₁₆H₁₇O₂N₃ (ESI) m/e 284 (M+H)⁺.

[1127] To a stirred solution of the product from Step 35a (91 mg, 0.32mmol) in acetone (2 mL) is added a hot solution of fumaric acid (37 mg,0.32 mmol) in IPA (2 mL). The mixture is stirred for 30 min in a 50° C.water bath. The solvents are removed in vacuo and the remaining residueis dissolved in acetone (5 mL). The mixture is stirred overnight at rt.The solid precipitate is collected by filtration and washed withacetone. The solid is dried in vacuo overnight to give 96 mg (75%) ofExample 35 as a white solid: ¹H NMR (DMSO-d₆) δ9.1, 7.9, 7.8, 7.5, 7.4,6.5, 3.8, 3.1, 3.0-2.8, 2.6, 1.7, 1.3.

[1128] The following examples can be prepared using the couplingprocedure for Example 35, making non-critical variations and using theappropriate carboxylic acids.

EXAMPLE 36

[1129]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-phenyl-1,3-oxazole-5-carboxamide(from 2-phenyl-1,3-oxazole-5-carboxylic acid, see Belen'kii, L. I.;Cheskis, M. A.; Zvolinskii, V. P.; Obukhov, A. E. Chem. Heterocycl.Compd. (Engl. Transl.); 22; 1986; 654-663).

EXAMPLE 37

[1130]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-phenyl-1,3-oxazole-4-carboxamide(from 2-phenyl-1,3-oxazole-4-carboxylic acid, see Korte, F.; Stoeriko,K. Chem. Ber.; 93; 1960; 1033-1042).

EXAMPLE 38

[1131]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-phenylisoxazole-3-carboxamide(from 5-phenylisoxazole-3-carboxylic acid, see Vaughan, W. R.; Spencer,J. L. J. Org. Chem.; 25; 1960; 1160-1164).

EXAMPLE 39

[1132]N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-thiophene-2-carbothioamide:

[1133] Step 39a

[1134] To a cooled (−10 to 0° C.) solution of n-BuLi (22.7 mL, 33.4mmol) in THF (10 mL) is added dropwise a solution of 2-phenyl-thiophene(5.46 g, 34.0 mmol) in THF (15 mL). The resulting green solution isstirred at 0° C. After 30 minutes, a solution of copper (I) bromide(0.87 g, 6.1 mmol) and lithium bromide (1.29 g, 14.9 mmol) in THF (20mL) is added to the cooled reaction solution over several minutes. Theresulting dark green solution is stirred at 0° C. for 15 minutes, atwhich time, carbon disulfide (2.0 mL, 34.0 mmol) is added dropwise over15 minutes. The resulting dark brown solution is stirred for 30 minutes,then iodomethane (2.9 mL, 46.4 mmol) is added dropwise to the reactionsolution over 5 minutes. The resulting dark brown solution is allowed towarm to room temperature and stirred for 1 hour, then is quenched with asolution of potassium cyanide in water (100 mL). The biphasic mixturewas diluted with EtOAc and washed with brine, dried over MgSO₄,filtered, and concentrated to give a dark orange solid (8.5 grams) whichis purified with flash chromatography on silica gel (eluent: gradient ofheptane to 2% THF/heptane) to give methyl5-phenyl-thiophene-2-carbodithioate as an orange solid. Yield 34%. HRMS(FAB) calculated for C₁₂H₁₀S₃+H 251.0023, found 251.0023.

[1135] Example 39 can be obtained using coupling procedures discussedherein.

EXAMPLE 40

[1136]N-[(exo)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide:

[1137] A mixture of exo-[3.2.1]-Amine (0.270 g, 1.36 mmol),5-phenyl-1,3-oxazole-2-carboxylic acid (see: Saito, S.; Tanaka, C., J.Pharm. Sci. Japan, 76, 1956, 305-7) (0.256 g, 1.36 mmol), THF (15 mL),DIEA (0.7 mL, 4.10 mmol), and DMF (4 mL) is cooled in an ice bath andtreated with HATU (0.516 g, 1.36 mmol). The mixture warmed to rt and isevaporated. The residue is diluted with CHCl₃ and washed with aqueousNaOH (1N). The organic layer is dried (MgSO₄), filtered, evaporated, andthe resulting oil purified by flash column chromatography (1:6:90; conc.NH₄OH—MeOH—CHCl₃). The hydrochloride salt is formed and triturated withEtOAc/hexane to yield Example 40 (0.246 g, 54%). MS for C₁₇H₁₉N₃O₂.HCl(ESI) (MH)⁺ m/z=298.

EXAMPLE 41

[1138]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromothiophene-2-carboxamidehydrochloride:

[1139] The free base of Example 41 is obtained following the proceduresfor Example 40, and using 3R,5R-[3.2.1]-Amine as the amine. The freebase is treated with MeOH/HCl, evaporated, triturated (EtOH/Et₂O) anddried in vaccuo to afford Example 41 as a solid in 87% yield from thecoupling: ¹H NMR (400 MHz, DMSO-d₆) d 10.61, 8.70-8.85, 7.71, 7.31,4.30-4.55, 3.05-3.55, 2.65-2.75, 2.00-2.20, 1.80-1.95, 1.65-1.80.

EXAMPLE 42

[1140]N-[(3R,5R)-1-Azabicyclo[3.2.1]oct-3-yl]-5-phenyl-2-furan-carboxamidehydrochloride:

[1141] The free base of Example 42 is obtained following Example 40, andusing 3R,5R-[3.2.1]-Amine as the amine. The crude material is treatedwith MeOH/HCl, evaporated, triturated (Et₂O) and dried in vaccuo toafford Example 42 as a foam in 68% yield from the coupling; ¹NMR (400MHz, DMSO-d₆) d 8.35-8.45, 7.90; 7.49; 7.39; 7.23; 7.12; 4.40-4.65,3.05-3.55, 2.65-2.75, 2.05-2.20, 1.85-2.00, 1.75-1.85

EXAMPLE 43

[1142]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)-furan-2-carboxamidehydrochloride:

[1143] The free base of Example 43 is obtained following Example 40, andusing 3R,5R-[3.2.1]-Amine as the amine. The crude material is treatedwith MeOH/HCl, evaporated, triturated (EtOH/Et₂O) and dried in vaccuo toafford Example 43 as a solid in 72% yield from the coupling: ¹NMR (400MHz, DMSO-d₆) d 10.75, 8.50-8.65, 8.13, 7.35-7.55, 7.29, 6.97,4.40-4.60, 3.10-3.60, 2.65-2.80, 2.05-2.22, 1.75-2.05

EXAMPLE 44

[1144]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1,3-oxazole-2-carboxamidehydrochloride:

[1145] A mixture of 5-phenyl-1,3-oxazole-2-carboxylic acid (0.241 g),3R,5R-[3.2.1]-Amine (0.221 g), ethanol (7 mL) and sodium ethoxide (0.153g) is heated at 100° C. After 36 h, the mixture is concentrated andpartitioned between EtOAc and H₂O. The organic layers are separated,dried (MgSO₄), filtered and concentrated. The crude product ischromatographed (Biotage 40S, (1:9:89) NH₄OH—MeOH—CHCl3). The productfractions are pooled, concentrated, treated with EtOH, and concentratedagain. The residue is treated with MeOH/HCl, evaporated, triturated(EtOH/Et₂O) and dried in vaccuo to afford 0.128 g (35%) of Example 44 asa solid: ¹H NMR (400 MHz, DMSO-d₆) d 10.67, 8.95-9.05, 7.95, 7.83, 7.54,7.46, 4.40-4.55, 3.05-3.60, 2.65-2.75, 2.05-2.20, 1.75-2.00.

EXAMPLE 45

[1146]5-[4-(acetylamino)phenyl]-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide(2E)-but-2-enedioic acid:

[1147] A mixture of 3R,5R-[3.2.1]-Amine (0.600 g), ethyl5-(4-nitrophenyl)-1,3-oxazole-2-carboxylate (1.11 g), ethanol (20 mL)and sodium ethoxide (0.429 g) is heated in a 100° C. oil bath for 16 h.Then additional ethyl 5-(4-nitrophenyl)-1,3-oxazole-2-carboxylate (0.111g) is added and heating continued for 4 h. The mixture is cooled,concentrated and the residue partitioned between EtOAc/1 N NaOH. Theorganic layer is separated, dried (MgSO₄), filtered and evaporated. Theresidue is chromatographed (Biotage 40S, 1:10:89-NH₄OH—MeOH—CHCl₃) andproduct fractions pooled and concentrated to afford 0.463 g of theintermediateN-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-nitrophenyl)-1,3-oxazole-2-carboxamideas a solid: MS (ESI+) m/z (MH+) 343.

[1148] A mixture of nitro intermediate (0.444 g), 10% Pd/C (0.223 g) andMeOH (40 mL) is shaken under H₂ (45 PSI) for 16 h. The mixture is thenfiltered through Celite and HCl in methanol is added. The mixture isconcentrated to give 0.286 g of Example 165 as a solid: MS (ESI+) m/z(MH+) 313.

[1149] An ice chilled suspension of5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide(0.294 g), CH₂Cl₂ (20 mL), and acetyl chloride (0.07 mL) is treated withTEA (0.59 ml) under N₂. Additional acetyl chloride (0.02 mL) is addedand the mixture allowed to warm to rt overnight. After 16 h, the mixtureis diluted with water (˜10 mL) and 1 N NaOH (˜2 mL). The organic layeris collected, dried (MgSO₄), filtered and chromatographed (Biotage 40 S,1:9:90-NH₄OH:MeOH:CHCl₃). The product fractions are pooled,concentrated, treated with 1.0 eq. fumaric acid, and EtOH (˜10 ml). Themixture is concentrated and the resulting solid was triturated withEtOH/Et₂O. The solid is collected and dried in a vacuum oven at 50° C.overnight to afford 0.069 g of Example 45 as a solid: ¹H NMR (400 MHz,DMSO-d₆) d 10.19, 8.70-8.80, 7.70-7.85, 6.49, 4.20-4.35, 3.44,2.90-3.15, 2.75-2.90, 2.60-2.70, 2.40-2.50, 2.07, 1.70-1.90, 1.05.

EXAMPLE 46

[1150] N-(1-azabicyclo[3.2.2]non-3-yl)-5-bromothiophene-2-carboxamide4-methylbenzenesulfonate:

[1151] To a stirred solution of [3.2.2]-Amine (310 mg, 0.64 mmol) in DMF(8.0 mL) in a 0° C. ice bath is added sequentially DIEA (334 μL, 1.92mmol), 5-bromothiophene-2-carboxylic acid (140 mg, 0.67 mmol) and HATU(243 mg, 0.64 mmol). The mixture is stirred in the 0° C. ice bath for 15min, followed by warming to rt and stirring overnight. The mixture isconcentrated in vacuo to a brown residue. The residue is partitionedbetween saturated aqueous potassium carbonate solution and CHCl₃—MeOH(90:10). The aqueous layer is extracted with CHCl₃—MeOH (90:10), and thecombined organic layers are washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The crude product is purifiedby flash chromatography on silica gel. Elution with CHCl₃—MeOH—NH₄OH(95:4.5:0.5) to give 119 mg (56%) of a solid.

[1152] To a stirred solution of the solid (19 mg, 0.36 mmol) in acetoneis added p-toluenesulfonic acid mono hydrate (69 mg, 0.36 mmol). Thesolution is heated in a water bath at 45° C. for 30 min, followed byconcentration of the solvent in vacuo. EtOAc (3.0 mL) is added to theresidue, which caused a solid to precipitate. The solid is filtered anddried in vacuo to give 164 mg (87%) of Example 46 as a white solid: ¹HNMR (CD₃OD) δ8.4, 7.7, 7.5, 7.3, 7.2, 4.6, 3.8, 3.6, 3.5, 3.4, 3.2,2.4-2.3, 2.2-2.0, 1.9.

[1153] Materials and Methods for Determining α7 nAChR Agonist Activity

[1154] Cell-based Assay for Measuring the EC₅₀ of α7 nAChR Agonists

[1155] Construction and Expression of the α7-5HT₃ Receptor:

[1156] The cDNA encoding the N-terminal 201 amino acids from the humanα7 nAChR that contain the ligand binding domain of the ion channel isfused to the cDNA encoding the pore forming region of the mouse 5HT₃receptor as described by Eisele J L, et al., Chimaericnicotinic-serotonergic receptor combines distinct ligand binding andchannel specificities, Nature (1993), December 2;366(6454):479-83, andmodified by Groppi, et al., WO 00/73431. The chimeric α7-5HT₃ ionchannel is inserted into pGS175 and pGS179 which contain the resistancegenes for G-418 and hygromycin B, respectively. Both plasmids weresimultaneously transfected into SH-EP1 cells and cell lines wereselected that were resistant to both G-418 and hyrgromycin B. Cell linesexpressing the chimeric ion channel were identified by their ability tobind fluorescent (α-bungarotoxin on their cell surface. The cells withthe highest amount of fluorescent α-bungarotoxin binding were isolatedusing a Fluorescent Activated Cell Sorter (FACS). Cell lines that stablyexpressed the chimeric α7-5HT₃ were identified by measuring fluorescentα-bungarotoxin binding after growing the cells in minimal essentialmedium containing nonessential amino acids supplemented with 10% fetalbovine serum, L-glutamine, 100 units/ml penicillin/streptomycin, 250ng/mg fungizone, 400 μg/ml hygromycin B, and 400 μg/ml G-418 at 37° C.with 6% CO₂ in a standard mammalian cell incubator for at least 4 weeksin continuous culture.

[1157] Assay of the Activity of the Chimeric α7-5HT₃ Receptor

[1158] To assay the activity of the α7-5HT₃ ion channel, cellsexpressing the channel were plated into each well of either a 96 or 384well dish (Corning #3614) and grown to confluence prior to assay. On theday of the assay, the cells were loaded with a 1:1 mixture of 2 mMCalcium Green 1, AM (Molecular Probes) dissolved in anhydrous DMSO and20% pluronic F-127 (Molecular Probes). This solution is added directlyto the growth media of each well to achieve a final concentration 2 μM.The cells were incubated with the dye for 60 min at 37° C. and thenwashed with a modified version of Earle's balanced salt solution(MMEBSS) as described in WO 00/73431. The ion conditions of the MMEBSSis adjusted to maximize the flux of calcium ion through the chimericα7-5HT₃ ion channel as described in WO 00/7343 1. The activity ofcompounds on the chimeric α7-5HT₃ ion channel is analyzed on FLIPR. Theinstrument is set up with an excitation wavelength of 488 nanometersusing 500 milliwatts of power. Fluorescent emission is measured above525 nanometers with an appropriate F-stop to maintain a maximal signalto noise ratio. Agonist activity of each compound is measured bydirectly adding the compound to cells expressing the chimeric α7-5HT₃ion channel and measuring the resulting increase in intracellularcalcium that is caused by the agonist-induced activation of the chimericion channel. The assay is quantitative such that concentration-dependentincrease in intracelluar calcium is measured as concentration-dependentchange in Calcium Green fluorescence. The effective concentration neededfor a compound to cause a 50% maximal increase in intracellular calciumis termed the EC₅₀. The following examples of the present invention haveEC₅₀ values from about 30 nM to about 16,000 nM: Examples 1-3, 11,25-29, 30, 35, 40-46.

[1159] Binding Constants:

[1160] Another way for measuring α7 nAChR agonist activity is todetermine binding constants of a potential agonist in a competitionbinding assay. For α7 nAChR agonists, there is good correlation betweenfunctional EC₅₀ values using the chimeric α7-5HT₃ ion channel as a drugtarget and binding affinity of compounds to the endogenous α7 nAChR.

[1161] Membrane Preparation.

[1162] Male Sprague-Dawley rats (300-350 g) are sacrificed bydecapitation and the brains (whole brain minus cerebellum) are dissectedquickly, weighed and homogenized in 9 volumes/g wet weight of ice-cold0.32 M sucrose using a rotating pestle on setting 50 (10 up and downstrokes). The homogenate is centrifuged at 1,000×g for 10 minutes at 4°C. The supernatant is collected and centrifuged at 20,000×g for 20minutes at 4° C. The resulting pellet is resuspended to a proteinconcentration of 1-8 mg/mL. Aliquots of 5 mL homogenate are frozen at−80° C. until needed for the assay. On the day of the assay, aliquotsare thawed at rt and diluted with Kreb's—20 mM Hepes buffer pH 7.0 (atrt) containing 4.16 mM NaHCO₃, 0.44 mM KH₂PO₄, 127 mM NaCl, 5.36 mM KCl,1.26 mM CaCl₂, and 0.98 mM MgCl₂, so that 25-150 μg protein are addedper test tube. Proteins are determined by the Bradford method (Bradford,M. M., Anal. Biochem., 72, 248-254, 1976) using bovine serum albumin asthe standard.

[1163] Binding Assay.

[1164] For saturation studies, 0.4 mL homogenate are added to test tubescontaining buffer and various concentrations of radioligand, and areincubated in a final volume of 0.5 mL for 1 hour at 25° C. Nonspecificbinding is determined in tissues incubated in parallel in the presenceof 0.05 mls MLA for a final concentration of 1 μM, added before theradioligand. In competition studies, drugs are added in increasingconcentrations to the test tubes before addition of 0.05 mls [³H]-MLAfor a final concentration 3.0 to 4.0 nM. The incubations are terminatedby rapid vacuum filtration through Whatman GF/B glass filter papermounted on a 48 well Brandel cell harvester. Filters are pre-soaked in50 mM Tris HCl pH 7.0-0.05% polyethylenimine. The filters are rapidlywashed two times with 5 mL aliquots of cold 0.9% saline and then countedfor radioactivity by liquid scintillation spectrometry.

[1165] Data Analysis.

[1166] In competition binding studies, the inhibition constant (Ki) iscalculated from the concentration dependent inhibition of [³H]-MLAbinding obtained from non-linear regression fitting program according tothe Cheng-Prusoff equation (Cheng, Y. C. and Prussoff, W. H., Biochem.Pharmacol., 22, p. 3099-3108, 1973). Hill coefficients were obtainedusing non-linear regression (GraphPad Prism sigmoidal dose-response withvariable slope).

What is claimed:
 1. A compound of Formula I:Azabicyclo—N(R₁)—C(═X)—W  Formula I wherein, X is O or S; R₁ is H,alkyl, cycloalkyl, halogenated alkyl, or aryl; W is a cyclicheteroaromatic moiety where the heteroatoms can be from 1-2 atomsselected from oxygen, sulfur, or nitrogen of the following structures:

wherein U is —O—, —S—, or —N(Ru)—; V and Y are independently ═N—, or═C(R_(VY))—; Z is ═N—, or ═CH—, provided that when both V and Y are═C(R_(VY))— and Z is ═CH—, only one ═C(R_(VY))— can be ═CH—, furtherprovided that when U is —O—, Y is —C(R_(VY))— and Z is ═C(H)—, V cannotbe ═N—, and further provided that no more than one of V, Y, or Z is aheteroatom; R_(U) is H, alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substitutedalkyl, limited substituted alkyl, substituted cycloalkyl, substitutedheterocycloalkyl, aryl, or —SO₂R₈, and provided that when W is (b) and Zis ═N— and U is N(R_(U)), R_(U) cannot be phenyl or substituted phenyl;Each R_(VY) is independently H, alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated alkenyl, halogenatedalkynyl, halogenated cycloalkyl, halogenated heterocycloalkyl,substituted alkyl, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted heterocycloalkyl, limited substituted alkyl,limited substituted alkenyl, limited substituted alkynyl, aryl, —OR₈,—OR₁₄, —SR₈, —SR₁₄, F, Cl, Br, I, —NR₈R₈, —NR₁₄R₁₄, —C(O)R₈, —C(O)R₁₄,—C(O)NR₈R₈, —C(O)NR₁₄R₁₄, —C(R₆)═N(R₁₆), —CN, —NR₈C(O)R₁₁,—S(O)₂NR₈R₈,—OS(O)₂R₁₁, —S(O)₂R₈, —S(O)₂R₁₄, —NR₈S(O)₂R₈, —N(H)C(O)N(H)R₈, —NO₂, R₇,R₉, and 0-3 substituents independently selected from F, Cl, Br, I, orR₁₅, and 0-3 substituents independently selected from F, Cl, Br, I, orR₁₅; Azabicyclo is

R₀ is H, lower alkyl, substituted lower alkyl, or halogenated loweralkyl; R₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,aryl or R₂ is absent provided that k₂, k₅, or k₆ is 0; k₂ is 0 or 1; k₅and k₆ are independently 0, 1, or 2; R₂₋₃ is H, alkyl, halogenatedalkyl, substituted alkyl, F, Cl, Br, or I; R₆ is H, F, Cl, CN, alkyl,substituted alkyl, cycloalkyl, halogenated alkyl, and aryl; R₇ is5-membered heteroaromatic mono-cyclic moieties containing within thering 1-3 heteroatoms independently selected from the group consisting of—O—, ═N—, —N(R₁₉)—, and —S—, and having 0-1 substituent selected fromR₂₀ and further having 0-3 substituents independently selected from F,Cl, Br, or I, or R₇ is a 9-membered fused-ring moiety having a6-membered ring fused to a 5-membered ring and having the formula

wherein A₁ is O, S, or NR₁₉, wherein A is CR₁₈ or N, A₂ and A₃ areindependently selected from CR₁₈, C(R₁₈)₂, O, S, N, or NR₁₉, providedthat both A₂ and A₃ are not simultaneously O, simultaneously S, orsimultaneously O and S, or

wherein A is CR₁₈, or N, A₂ and A₃ are independently selected from CR₁₈,C(R₁₈)₂, O, S, N, or NR₁₉, each 9-membered fused-ring moiety having 0-1substituent selected from R₂₀ and further having 0-3 substituent(s)independently selected from F, Cl, Br, or I, and having a bond directlyor indirectly attached to the core molecule where valency allows ineither the 6-membered or the 5-membered ring of the fused-ring moiety;Each R₈ is independently H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, R₉, phenyl, or substituted phenyl; R₉ is6-membered heteroaromatic mono-cyclic moieties containing within thering 1-3 heteroatoms selected from ═N— and having 0-1 substituentselected from R₂₀ and 0-3 substituent(s) independently selected from F,Cl, Br, or I, or R₉ is 10-membered heteroaromatic bi-cyclic moietiescontaining within one or both rings 1-3 heteroatoms selected from ═N—,including, but not limited to, quinolinyl or isoquinolinyl, each10-membered fused-ring moiety having 0-1 substituent selected from R₂₀and 0-3 substituent(s) independently selected from F, Cl, Br, or I, andhaving a bond directly or indirectly attached to the core molecule wherevalency allows; Each R₁₀ is independently H, alkyl, cycloalkyl,heterocycloalkyl, alkyl substituted with 1 substituent selected fromR₁₃, cycloalkyl substituted with 1 substituent selected from R₁₃,heterocycloalkyl substituted with 1 substituent selected from R₁₃,halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,phenyl, R₇, R₉, or phenyl having 1 substituent selected from R₂₀ andfurther having 0-3 substituents independently selected from F, Cl, Br,or I; Each R₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, or halogenatedheterocycloalkyl; R₁₃ is —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁,—CN, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, —CF₃, or —NO₂; Each R₁₄is independently H, alkyl, halogenated alkyl, limited substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, or substitutedheterocycloalkyl; R₁₅ is alkyl, substituted alkyl, halogenated alkyl,—OR₁₁, —CN, —NO₂, —NR₁₀R₁₀; R₁₆ is —OR₁₇, —NR₁₇R₁₇, —NR₁₇C(O)R₁₇,—NR₁₇S(O)₂R₁₇, —N(R₁₇)C(O)NR₁₇R₁₇, —NR₁₇C(O)OR₁₇; R₁₇ is H, alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl,halogenated heterocycloalkyl, substituted alkyl, substituted alkenyl,substituted alkynyl, substituted cycloalkyl, substitutedheterocycloalkyl, phenyl, phenyl having 1-4 substituents independentlyselected from F, Cl, Br, I and R₁₅, naphthyl, or naphthyl having 1-4substituents independently selected from F, Cl, Br, I and R₁₅; Each R₁₈is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substitutedalkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR₁₁,—SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,—S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, F, Cl, Br, or I, or a bond directly orindirectly attached to the core molecule, provided that there is onlyone said bond to the core molecule within the 9-membered fused-ringmoiety, further provided that the fused-ring moiety has 0-1 substituentselected from alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR ₁₁,—NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,—S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁, and further provided that thefused-ring moiety has 0-3 substituent(s) selected from F, Cl, Br, or I;R₁₉ is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, phenyl, —SO₂R₈, orphenyl having 1 substituent selected from R₂₀ and further having 0-3substituents independently selected from F, Cl, Br, or I; R₂₀ is alkyl,cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,halogenated heterocycloalkyl, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁,—C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, —NO₂,alkyl substituted with 1-4 substituent(s) independently selected from F,Cl, Br, I, or R₁₃, cycloalkyl substituted with 1-4 substituent(s)independently selected from F, Cl, Br, I, or R₁₃, or heterocycloalkylsubstituted with 1-4 substituent(s) independently selected from F, Cl,Br, I, or R₁₃; or pharmaceutically acceptable salt, racemic mixture, orpure enantiomer thereof.
 2. The compound of claim 1, wherein X is O. 3.The compound of claim 2, wherein R₁ is H, alkyl, or cycloalkyl.
 4. Thecompound of claim 3, wherein W is (a).
 5. The compound of claim 4,wherein (a) is thiophen-2-yl, furan-2-yl, 1,3-thiazol-5-yl,1,3-oxazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-oxadiazol-2-yl,1,3-oxazol-5-yl, 1H-pyrrol-2-yl, or 1,2,4-oxadiazol-5-yl, any of whichis optionally substituted on carbon independently with alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenatedalkenyl, halogenated alkynyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, substituted alkenyl, substitutedalkynyl, substituted cycloalkyl, substituted heterocycloalkyl, limitedsubstituted alkyl, limited substituted alkenyl, limited substitutedalkynyl, aryl, —OR₈, —OR₁₄, —SR₈, —SR₁₄, F, Cl, Br, I, —NR₈R₈, —NR₁₄R₁₄,—C(O)R₈, —C(O)R₁₄, —C(O)NR₈R₈, —C(O)NR₁₄R₁₄, —C(R₆)═N(R₁₆), —CN,—NR₈C(O)R₁₁, —S(O)₂NR₈R₈, —OS(O)₂R₁₁, —S(O)₂R₈, —S(O)₂R₁₄, —NR₈S(O)₂R₈,—N(H)C(O)N(H)R₈, —NO₂, R₇, R₉, and 0-3 substituents independentlyselected from F, Cl, Br, I, or R₁₅, and 0-3 substituents independentlyselected from F, Cl, Br, I, or R₁₅; and further optionally substitutedon nitrogen with alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,limited substituted alkyl, substituted cycloalkyl, substitutedheterocycloalkyl, aryl, or —SO₂R₈.
 6. The compound according to claim 5,wherein (a) is thiophen-2-yl, furan-2-yl, 1,3-thiazol-2-yl,1,3-oxazol-2-yl, or 1H-pyrrol-2-yl, any of which is optionallysubstituted with up to 2 substituents wherein the substituents arebromo, chloro, methyl, phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl,2-acetylaminophenyl, 3-acetylaminophenyl, 4-acetylaminophenyl,2-trifluoroacetamidophenyl, 3-trifluoroacetamidophenyl,4-trifluoroacetamidophenyl, or pyridinyl.
 7. The compound of claim 6,wherein R₁ is H or lower alkyl.
 8. The compound of claim 7, whereinAzabicyclo is II or V.
 9. The compound of claim 8, wherein R₂ is loweralkyl or is absent provided that k₂ or k₅ is
 0. 10. The compound ofclaim 9, wherein the compound isN-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromothiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-bromothiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(pyridin-2-yl)-thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenylthiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide;5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 11. Thecompound of claim 9, wherein the compound isN-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-chlorothiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-methylthiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenylthiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;5-(2-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;5-(3-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;5-(2-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;5-(3-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;5-(4-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 12. Thecompound of claim 9, wherein the compound isN-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromo-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-chloro-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-methyl-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-fluorophenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-fluorophenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-chlorophenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-chlorophenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-chlorophenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methoxyphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methoxyphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methoxyphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methylphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methylphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methylphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-hydroxyphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-hydroxyphenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-hydroxyphenyl)-2-furamide;5-(2-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;5-(3-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;5-(2-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;5-(3-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;5-(4-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 13. Thecompound of claim 9, wherein the compound isN-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromo-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-chloro-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-methyl-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;5-(2-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(3-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(4-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 14. Thecompound of claim 9, wherein the compound isN-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-bromo-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-chloro-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-methyl-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;5-(2-aminophenyl)-N-[(3R,5R)-1-azabiyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(3-aminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1H-pyrrole-2-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-5-phenyl-1-methyl-1H-pyrrole-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 15. Thecompound of claim 9, wherein the compound isN-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-chlorothiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-methylthiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;5-(2-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;5-(3-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;5-(4-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;5-(2-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;5-(3-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;5-(4-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 16. Thecompound of claim 9, wherein the compound isN-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-chloro-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-methyl-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-chlorophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-chlorophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methoxyphenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methoxyphenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methoxyphenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylphenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methylphenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-hydroxyphenyl)-2-furamide;5-(2-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;5-(3-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;5-(4-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;5-(2-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;5-(3-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;5-(4-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 17. Thecompound of claim 9, wherein the compound isN-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-chloro-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-methyl-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)-1,3-thiazole-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;5-(2-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;5-(3-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;5-(4-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 18. Thecompound of claim 9, wherein the compound isN-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-bromo-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-chloro-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-methyl-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;5-(2-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;5-(3-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;5-(4-aminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1-pyrrole-2-carboxamide;N-[(exo-4(S))-1-azabicyclo[2.2.1]hept-3-yl]-5-phenyl-1-methyl-1-pyrrole-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 19. Thecompound of claim 7, wherein Azabicyclo is I, III, IV, or VI.
 20. Thecompound of claim 19, wherein R₂₋₃ is H or lower alkyl and wherein R₂ islower alkyl or R₂ is absent provided that k₆ is
 0. 21. The compound ofclaim 20, wherein the compound isN-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-bromothiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-chlorothiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-methylthiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenylthiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;5-(2-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;5-(3-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;5-(4-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;5-(2-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;5-(3-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;5-(4-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-methyl-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-hydroxyphenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-hydroxyphenyl)-2-furamide;5-(2-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;5-(3-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;5-(4-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;5-(2-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;5-(3-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;5-(4-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-methyl-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;5-(2-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(3-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(4-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-methyl-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;5-(2-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(3-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(4-aminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1-pyrrole-2-carboxamide;N-[(3R)-6-methyl-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1-methyl-1-pyrrole-2-carboxamide;N-[(3R)-1-azabicyclo[3 .2.2]non-3-yl]-5-phenyl-1,3-oxazole-2-carboxamide; or a pharmaceuticallyacceptable salt thereof, provided that the compound is the pureenantiomer or racemic mixture thereof.
 22. The compound of claim 20,wherein the compound isN-[2-azabicyclo[2.2.1]hept-5-yl]-5-bromothiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-chlorothiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-methylthiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenylthiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-bromo-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-chloro-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-methyl-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-fluorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-fluorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-fluorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-chlorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-chlorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-chlorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methoxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methoxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methoxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methylphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methylphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methylphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-hydroxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-hydroxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-hydroxyphenyl)-2-furamide;5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-bromo-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-chloro-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-methyl-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-bromo-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-chloro-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-methyl-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-y]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-5-yl]-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-1-pyrrole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-5-yl]-5-phenyl-1-methyl-1-pyrrole-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 23. Thecompound of claim 20, wherein the compound isN-[2-azabicyclo[2.2.1]hept-6-yl]-5-bromothiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-chlorothiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-methylthiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenylthiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-fluorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-fluorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-fluorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-chlorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-chlorophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methoxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methoxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methoxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methylphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methylphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methylphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-hydroxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-hydroxyphenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-hydroxyphenyl)thiophene-2-carboxamide;5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-trifluoroacetamidophenyl)thiophene-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-bromo-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-chloro-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-methyl-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-fluorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-fluorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-fluorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-chlorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-chlorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-chlorophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methoxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methoxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methoxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methylphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methylphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methylphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-hydroxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-hydroxyphenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-hydroxyphenyl)-2-furamide;5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-trifluoroacetamidophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-trifluoroacetamidophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-trifluoroacetamidophenyl)-2-furamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-bromo-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-chloro-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-methyl-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methoxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-hydroxyphenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-trifluoroacetamidophenyl)-1,3-thiazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-bromo-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-chloro-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-methyl-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-fluorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;5-(2-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;5-(3-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;5-(4-aminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;5-(2-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;5-(3-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;5-(4-acetylaminophenyl)-N-[2-azabicyclo[2.2.1]hept-6-yl]-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(2-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(3-trifluoroacetamidophenyl)-1,3-oxazole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-(4-trifluoroacetamidophenyl)-1,3-oxazole-2carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-1H-pyrrole-2-carboxamide;N-[2-azabicyclo[2.2.1]hept-6-yl]-5-phenyl-1-methyl-1H-pyrrole-2-carboxamide;or a pharmaceutically acceptable salt thereof, provided that thecompound is the pure enantiomer or racemic mixture thereof.
 24. Apharmaceutical composition comprising a compound according to claim 1,an anti-psychotic agent, and a pharmaceutically acceptable excipient.25. The pharmaceutical composition according to claim 24, wherein saidcompound and said agent are to be independently administered rectally,topically, orally, sublingually, or parenterally for a therapeuticallyeffective interval.
 26. The pharmaceutical composition according toclaim 24, wherein said compound is administered in an amount of fromabout 0.001 to about 100 mg/kg of body weight of said mammal per day.27. The pharmaceutical composition according to claim 24, wherein saidcompound is administered in an amount of from about 0.1 to about 50mg/kg of body weight of said mammal per day.
 28. The pharmaceuticalcomposition according to claim 24, comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.
 29. Thepharmaceutical composition according to claim 28, wherein said compoundis administered rectally, topically, orally, sublingually, orparenterally for a therapeutically effective interval.
 30. Thepharmaceutical composition according to claim 28, wherein said compoundis administered in an amount of from about 0.001 to about 100 mg/kg ofbody weight of said mammal per day.
 31. The pharmaceutical compositionaccording to claim 28, wherein said compound is administered in anamount of from about 0.1 to about 50 mg/kg of body weight of said mammalper day.
 32. A method for treating a disease or condition in a mammal inneed thereof, wherein the mammal would receive symptomatic relief fromthe administration of an α7 nicotinic acetylcholine receptor agonistcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim
 1. 33. The method according toclaim 33, wherein the disease or condition is cognitive and attentiondeficit symptoms of Alzheimer's Disease, neurodegeneration associatedwith diseases such as Alzheimer's disease, pre-senile dementia (mildcognitive impairment), or senile dementia.
 34. The method according toclaim 33, wherein the disease or condition is schizophrenia orpsychosis.
 35. The method of claim 34, wherein the mammal would receivesymptomatic relief from the administration of a therapeuticallyeffective amount of α7 nicotinic acetylcholine receptor agonist and ananti-psychotic agent for a therapeutically effective interval.
 36. Themethod according to claim 33, wherein the disease or condition isdepression, or anxiety and general anxiety disorders and post traumaticstress disorder.
 37. The method according to claim 33, wherein thedisease or condition is attention deficit disorder, or attention deficithyperactivity disorder.
 38. The method according to claim 33, whereinthe disease or condition is mood and affective disorders, amyotrophiclateral sclerosis, borderline personality disorder, traumatic braininjury, behavioral and cognitive problems in general and associated withbrain tumors, AIDS dementia complex, dementia associated with Down'ssyndrome, dementia associated with Lewy Bodies, Huntington's disease,Parkinson's disease, tardive dyskinesia, Pick's disease, dysregulationof food intake including bulemia and anorexia nervosa, withdrawalsymptoms associated with smoking cessation and dependant drug cessation,Gilles de la Tourette's Syndrome, age-related macular degeneration,glaucoma, neurodegeneration associated with glaucoma, or symptomsassociated with pain.